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DR SUMIT KUMAR
Assistant professor
NEIGRIHMS, Shillong
? Mechanism
? After neoadjuvant chemotherapy
?After neoadjuvant endocrine therapy
?At the time of recurrence / metastasis
? After neoadjuvant her2 neu inhibitor
Prevalence of ERα+ Breast Cancer: ERα+ breast cancer accounts for 75% of all breast cancer cases,
with half also expressing PgR, forming HR-positive breast cancer.
Function of Estrogen Receptors: ERα promotes cancer cell growth through activation of genomic
and non-genomic pathways. ERβ can modulate ERα activity and counteract its effects.
Hormone Receptor (HR) Status: HR status, determined by ERα and PgR expression, is a key
prognostic and predictive factor in breast cancer.
HER2/neu Receptor: HER2/neu is another critical receptor in breast cancer. Overexpression or
amplification of HER2 is found in approximately 15-20% of breast cancers and is associated with
aggressive disease.
Significance of HR and HER2 Status: HR-positive breast cancer is associated with lower
proliferation rates, longer disease-free survival (DFS), and overall survival (OS). HER2-positive
cancers benefit from targeted therapies but are generally more aggressive.
Endocrine Therapy (ET): ETs, such as tamoxifen, fulvestrant, and aromatase inhibitors, target ERα
signaling and are standard treatments for HR+ breast cancer.
HER2-Targeted Therapies: HER2-positive cancers are treated with targeted therapies like
trastuzumab and pertuzumab, which specifically inhibit HER2 signaling.
Receptor Discordance: Changes in receptor status (e.g., from HR+ to HR− or HER2− to HER2+) can
occur during disease progression, impacting treatment decisions.
Mechanisms of Discordance: Receptor discordance can result from genetic mutations, epigenetic
modifications, and selective pressure from treatments.
Clinical Impact of Discordance: Regular reassessment of receptor status is essential to guide therapy
adjustments and improve patient outcomes, emphasizing the importance of advanced molecular
profiling to tailor personalized treatment strategies.
Genetic
Mechanisms
Epigenetic
Mechanisms
Growth
Factor
Signaling
Post-
Transcriptional
Regulation of
ERαExpression
Post-
Translational
Regulation of
ERαExpression
The Role
of Hypoxia
The Role of
BRCA1
Intratumor
Heterogeneity
Breast cancer :Receptor (ER/PR/HER2 NEU) Discordance.pptx
Breast cancer :Receptor (ER/PR/HER2 NEU) Discordance.pptx
• Encodes Estrogen Receptor Alpha
(ERα).
• Domains: AF1, DNA-binding (DBD),
Ligand-binding (LBD), AF2, Hinge.
• Binds estrogens (E2), homodimerizes,
and attaches to estrogen-responsive
elements (EREs) to activate gene
transcription.
Genetic Alterations:
• Mutations, deletions, insertions, loss
of heterozygosity (LOH).
• Can lead to functional loss and
therapy resistance.
•Encodes Progesterone Receptor (PgR)
with isoforms A and B.
•PgR expression is regulated by ERα.
• PgR-A: Repressor
• PgR-B: Activator
Genetic Alterations:
• LOH occurs in 18-40% of ERα+ breast
cancers.
• Often leads to loss of PgR expression
• Modulation: Cyclic
methylation/demethylation controls ERα
levels.
• Inhibition: Methylation blocks
transcription factors like AP2, preventing
ESR1 transcription.
• Complex Formation: ZEB1 with DNMT3B
and HDAC1 induces hypermethylation and
histone deacetylation, tightening
chromatin and reducing transcription.
•Repression: Loss of ERα signaling
decreases PGR transcription.
•Mechanism: Involves polycomb
repressors, histone deacetylases, and
promoter methylation.
•Impact: Hyper-methylation at key
sites occurs in ~40% of PgR- breast
cancers, leading to loss of PgR
expression.
Epigenetics involves changes in gene expression without altering the DNA sequence, primarily through mechanisms
like DNA methylation and histone modification, which regulate how genes are turned on or off.
These epigenetic changes contribute to hormone receptor loss and breast cancer progression.
• Growth factor signaling involves proteins (growth factors) that bind to receptors on the
cell surface, triggering a cascade of intracellular events that promote cell growth,
proliferation, and survival.
• The PI3K/AKT/mTORC1 and MAPK signaling pathways negatively correlate with ERα
expression. Loss of PTEN, an inhibitor of PI3K/AKT/mTORC1, is linked to the loss of ERα
and PgR in breast cancer.
• Around 30-40% of sporadic breast cancers show PTEN loss of heterozygosity (LOH), associated
with higher tumor grades and PgR loss.
with growth factors like IGF-I, EGF, and heregulin downregulates
PGR mRNA and PgR protein in cell lines.
result in MAPK hyperactivation and ERα downregulation.
HER2+ breast cancers express lower ERα levels and show resistance to endocrine
therapies without HER2 inhibition due to HER2-mediated signaling through
PI3K/AKT/mTORC1 and MAPK pathways.
leads to lower ESR1 gene expression in ERα+ PgR− cell
lines, but inhibition of this pathway can restore ERα expression, demonstrating its
reversible nature.
• NFkB, often constitutively active in ERα− breast cancers, correlates with lower ERα levels.
Its activation, possibly due to MAPK hyperactivation or PI3K/AKT/mTORC1 signaling,
further contributes to ERα downregulation.
• ESR1 mRNA is 4.3 kb long and contains a 3' untranslated region (UTR) with
AU-rich sequences that promote mRNA degradation.
• Changes in ESR1 mRNA structure can impact the translation of ERα,
though the exact mechanisms are still being studied.
• MicroRNAs (miRNAs) are small RNA molecules that regulate gene
expression. For instance:
• miR-222/221 targets ESR1 mRNA, leading to its degradation. Levels of these miRNAs
are higher in ERα− breast cancer cells compared to ERα+ cells.
• miR-206 and miR-92 also influence ERα and ERβ levels by binding to their respective
mRNA 3' UTRs.
• miR-27a targets ZBTB10, a protein involved in directly regulating ERα expression in
HR+ breast cancer cell lines.
• These miRNAs play a crucial role in fine-tuning ERα expression post-
transcriptionally, contributing to the complex regulation of hormone
receptor levels in breast cancer.
:
• ERα undergoes polyubiquitination and subsequent degradation via the ubiquitin
proteasome system (UPS) when bound to estradiol (E2).
• This process is mediated by E2-ERα complex binding to estrogen responsive
elements (EREs), recruiting E3-ubiquitin ligases.
• Selective estrogen receptor degraders (SERDs) like fulvestrant exploit ERα
polyubiquitination for therapeutic benefit in HR+/HER2− breast cancer.
Phosphorylation at specific residues modulates ERα ubiquitination:
• SRC-induced phosphorylation at Y537 residue promotes ERα ubiquitination and
degradation.
• Phosphorylation by GSK3, LMTK3, and ABL stabilizes ERα and enhances its
transcriptional activity.
:
• MUC1 stabilizes ERα binding to ERE promoters, enhancing ERα-induced gene
transcription; its knockdown reduces ERα levels in HR+ breast cancer cells.
• PIN1 inhibits ERα degradation by preventing E3 ligase interaction.
• RB protein interacts with ERα to regulate its stability; RB loss correlates with reduced
ERα levels in breast cancer cells.
• HSP90 and p23 chaperones protect ERα from UPS-mediated degradation.
• RNF31 mediates ERα monoubiquitination, stabilizing ERα and enhancing its activity.
• Palmitoylation stabilizes ERα and promotes its localization to the cell membrane,
activating oncogenic signaling.
These diverse post-translational modifications and interactions finely
regulate ERα levels and activity in breast cancer, impacting response to
hormonal therapies and disease progression.
Hypoxia in tumors results from rapid growth and poor vascularization.
• It promotes tumor cell growth, alters metabolism, and facilitates metastasis.
• Impact on ERα Expression:
• In HR+ breast cancer:
• Hypoxia reduces ERα protein levels by promoting its degradation via the proteasome.
• HIF-1α, a key regulator in hypoxia, may inhibit ESR1 gene transcription, contributing to
decreased ERα levels (Figure 1).
Research Challenges and Perspectives:
• The relationship between HIF-1α signaling and ERα expression needs
further clarification.
• Understanding hypoxia's influence on ERα sheds light on its role in breast
cancer progression and resistance to therapies.
• BRCA1 interacts with RNA polymerase II.
• Activates ESR1 gene transcription by binding to its promoter and recruiting Oct1.
• Loss of BRCA1 function leads to reduced ERα protein levels.
• Despite ERα-positive status, tumors may exhibit lower ERα expression due to
impaired transcriptional activation by BRCA1.
• BRCA1 promotes PgR protein degradation via ubiquitination.
• Induces chromatin silencing at PgR-regulated promoters through the BRCA1/BARD1
complex.
• BRCA gene mutations disrupt normal transcriptional regulation of hormone
receptors.
• Resultant hormone receptor discordance impacts treatment response and tumor
behavior.
• Definition: Accumulation of genetic mutations over time leading to the emergence of distinct tumor cell subclones.
• Impact: Results in variability in hormone receptor expression (e.g., ERα, PgR) among tumor cells within the same lesion.
• Changes: Alterations in DNA methylation and histone modifications.
• Effect: Influence gene expression patterns, contributing to phenotypic diversity including hormone receptor status.
• Factors: Variations in oxygen levels (hypoxia), nutrient availability, and pH within the tumor microenvironment.
• Contribution: Influence cellular behavior, survival, and adaptation of different tumor cell populations.
• Presence: Subpopulations of CSCs with self-renewal and differentiation capabilities.
• Role: Contribute to intratumoral heterogeneity by giving rise to diverse progeny with varying hormone receptor expression.
• Spatial Variability: Uneven distribution of tumor cells with different molecular profiles within the tumor mass.
• Temporal Changes: Dynamic alterations in molecular features over the course of tumor progression and treatment.
• The transition from HR negative to positive status in breast cancer
management can occur through several mechanisms, although it is generally
less common than the opposite scenario (HR positive to negative).
• some mechanisms that can contribute to this phenomenon:
Definition: Breast tumors are composed of heterogeneous cell populations. During
treatment, some HR-positive cells may survive while HR-negative cells are eliminated.
Mechanism: Chemotherapy or endocrine therapy can exert selective pressure on tumor
cells. HR-positive cells, which may have inherent or acquired resistance mechanisms,
survive treatment while HR-negative cells are eradicated.
Changes: Alterations in DNA methylation patterns or histone modifications.
Effect: These epigenetic modifications can potentially lead to reactivation of HR genes
(ESR1 for ERα or PGR for PgR), thereby switching the phenotype from HR-negative to
HR-positive.
Endocrine Therapy: Treatment with hormonal therapies (e.g., tamoxifen, aromatase
inhibitors) can alter the hormonal environment within the tumor.
Effect: This can influence the expression and activity of hormone receptors in surviving
tumor cells, potentially leading to a change in HR status from negative to positive.
Stromal Influences: Changes in the tumor microenvironment, such as interactions with immune cells or
fibroblasts, can impact tumor cell phenotype.
Induction: Certain signals within the microenvironment may induce or suppress the expression of
hormone receptors in tumor cells.
Acquisition of Mutations: Rarely, genetic mutations or alterations may occur during treatment that lead
to activation of HR genes in previously HR-negative cells.
Selective Advantage: Cells with these mutations may gain a growth advantage under the selective
pressure of therapy.
Diverse Cell Populations: Tumors are composed of heterogeneous cell populations with varying
molecular characteristics.
Survival of Subpopulations: HR-positive cells may exist as minor subpopulations within a predominantly
HR-negative tumor mass. Treatment can selectively eliminate HR-negative cells, allowing HR-positive
cells to proliferate and dominate the residual tumor.
Summary: Transition from HR-negative to HR-positive status during breast cancer management is a complex process
involving clonal selection, epigenetic changes, hormonal environment alterations, interactions with the tumor
microenvironment, genetic mutations, and intra-tumor heterogeneity. While less common than the reverse transition,
understanding these mechanisms can inform strategies for monitoring and managing breast cancer, particularly in cases
where HR status conversion impacts treatment decisions.
Data Details
Prognostic Impact of HR Loss
Conversion from ERα+ to ERα- status associated with a 48%
increase in risk of death compared to stable ERα+ status (HR
= 1.48, 95% CI 1.08-2.05).
PgR Loss and Clinical Behaviour
Loss of PgR in tumors with high ERα associated with more
aggressive behavior and resistance to SERMs.
Discordance Between Diagnostic and Surgical Samples
Low discordance rates: ERα 1.8%, PgR 15% between core
needle biopsy (CNB) and surgical samples in early-stage
breast cancer.
Discordance in Lymph Node Metastases
Rare discordance: ERα between primary tumors and axillary
lymph node metastases (2/50, 4%).
Technical Challenges in HR Assessment
Variability due to sampling methods (CNB vs. surgical
resection), delays in fixation, and IHC staining
reproducibility.
Standardization of HR Assessment
Improved reliability in determining ERα and PgR status with
standardized IHC techniques.
Impact of Decalcification on HR Assessment
Potential alteration of HR expression in bone metastases
due to decalcification of biopsy samples.
• Hormone Receptor (HR) status, including ER and PgR, is crucial in guiding
breast cancer treatment.
• HR status can change between primary and recurrent/metastatic tumors.
• Reassessment of HR status is important to tailor treatment plans and
improve patient outcomes.
• HR discordance rates between primary and recurrent/metastatic breast
cancer:
• ER status conversion: 14-24%
• PgR status conversion: 33%
• Discordance can involve conversion from HR+ to HR- or from HR- to HR+.
• HR status should be reassessed at the first recurrence or progression.
• Regular reassessment is recommended during subsequent progressions if clinically
indicated.
• Endocrine Therapy:
• Tamoxifen and aromatase inhibitors can lead to changes in ER and PgR expression.
• Neoadjuvant endocrine therapy may reduce ERα and PgR levels.
• Chemotherapy:
• Anthracyclines and taxanes have been associated with reductions in PgR expression
and changes in ER levels.
• Chemotherapy-induced epigenetic modifications may lead to HR status changes.
• Recommend biopsy of at least one metastatic site to reassess HR and HER2
status at first recurrence or progression.
• Suggest reevaluating ER, PgR, and HER2 status at recurrence or metastasis.
• Recommend mandatory reassessment of HR and HER2 status in metastatic
disease.
• Practical Considerations
• Use validated IHC techniques for HR testing.
• Ensure proper tissue handling and fixation.
• A multidisciplinary approach is essential for accurate interpretation and
treatment planning.
Breast cancer :Receptor (ER/PR/HER2 NEU) Discordance.pptx
HER2 Status in Breast Cancer: HER2 status is crucial for determining
treatment strategies and prognosis in breast cancer.
Definition of HER2 Discordance: Change in HER2 status between
primary and recurrent/metastatic tumors.
• Positive to Negative: Loss of HER2 expression in recurrent/metastatic tumors
previously HER2-positive.
• Negative to Positive: Gain of HER2 expression in recurrent/metastatic tumors
previously HER2-negative.
Importance of Discordance
• Impact on Treatment: Changes in HER2 status can lead to different
therapeutic approaches.
• Prognostic Value: Discordance can influence patient outcomes and guide
clinical decisions.
Primary mechanisms that can lead to changes in HER2 status from
positive to negative and vice versa
Mechanism Positive to Negative HER2 Neu Negative to Positive HER2 Neu
Tumor Heterogeneity
Loss of HER2 expression in some tumor
regions leading to overall negative status
Gain of HER2 expression in previously
HER2-negative regions
Clonal Evolution
Treatment pressure selecting for clones
without HER2 amplification
Emergence of new clones with HER2
amplification
Epigenetic Changes
DNA methylation silencing HER2 gene
expression
Epigenetic reprogramming leading to HER2
gene expression
Technical Factors
Variability in biopsy sampling, testing
techniques, and tissue handling leading to
misclassification
Initial false-negative result corrected upon
retesting
Genetic Instability
Mutations leading to loss of HER2 gene or
its expression
New mutations activating HER2 gene
Treatment-Induced Changes
Anti-HER2 therapies causing
downregulation or loss of HER2 expression
Other treatments reducing competition,
allowing HER2-expressing cells to
proliferate
Environmental Factors
Changes in tumor microenvironment
inhibiting HER2 expression
Changes in microenvironment favoring
HER2 expression
Loss of HER2 Gene Genetic deletion or loss of the HER2 gene Genetic amplification of the HER2 gene
: Reduction in HER2 protein expression while retaining ERBB2 gene amplification.
• Induction by Anti-HER2 Agents: Drugs like trastuzumab cause HER2 internalization and downregulation at
the membrane level.
1. Untreated HER2-Positive Tumors:
• HER2 gene amplification increases receptor expression.
• Promotes dimerization and activation of MAPK and PI3K/AKT/mTOR pathways.
2. Immune Cell Role:
• HER2 downregulation observed with trastuzumab when immune cells are involved.
• Interferon gamma (IFN-γ) from immune cells activates STAT1, leading to HER2 downregulation.
3. Combination Therapies:
• Trastuzumab and pertuzumab dual blockade increases HER2 downregulation.
• ADCs like trastuzumab emtansine (T-DM1) also induce downregulation, possibly leading to resistance.
4. Tyrosine Kinase Inhibitors (TKIs):
• TKIs prevent HER2 internalization, increasing surface HER2 expression.
• Combining TKIs with anti-HER2 antibodies enhances antitumor activity.
?
• Definition: Variability in HER2 expression within different areas of the same tumor.
2009: HER2 heterogeneity defined as 5%-50% tumor cells with:
• Ratio ≥ 2.2 (dual probes) or ≥ 6 HER2 signals/cell (single probes).
2013 Update: Adjusted cut-off to 10% and ratio to 2.0.
1.Filho et al. (2018):
• Evaluated 164 patients treated with T-DM1 and pertuzumab.
• Found 10% of samples were heterogeneous.
• Heterogeneous tumors had no complete response to treatment, while 55% of non-
heterogeneous tumors did.
• Most heterogeneous cases were IHC 2+ and ER-positive.
2.Caswell-Jin et al. (2019):
• Used whole-exome sequencing before and after treatment.
• Found new mutations in post-treatment samples, not present before treatment.
• Indicates resistant cells were selected by the treatment.
: HER2-Enriched (HER2-E) to Luminal A after neoadjuvant treatment
Cause: Decreased expression of cell proliferation genes post-treatment exposure
• Initially utilized microarray analysis (400+ genes)
• Currently employs PAM50 classifier for tumor subtyping
:
1. Neoadjuvant Treatment Studies:
• Significant subtype switch observed in many patients across different drug regimens
• HER2-E tumors frequently switch to Luminal A
2. Brasó-Maristany et al.:
• Subtype switch can be reversible after stopping anti-HER2 therapy
3. Pernas et al.:
• In a cohort of 26 patients with residual disease post-treatment:
• 81.8% HER2-E tumors switched to non-HER2-E subtypes
• 7 out of 26 patients converted to HER2-negative status
Breast cancer :Receptor (ER/PR/HER2 NEU) Discordance.pptx
Available online 21 November 2013
:
• Heterogeneity: I2 = 79%, p < 0.0001
• Primary vs. Distant Metastases: 41 (95% CI: 37–45)
• Primary vs. Loco-regional Relapse: 26 (95% CI: 21–32)
• Heterogeneity: I2 = 77%, p < 0.0001
• Primary vs. Distant Metastases: 10 (95% CI: 7–14)
• Primary vs. Loco-regional Relapse: 6 (95% CI: 3–9)
• IHC and FISH: 10 (95% CI: 7–12)
• IHC Only: 5 (95% CI: 2–8)
• Total Studies: 48
• Total Patients: 9926
Breast cancer :Receptor (ER/PR/HER2 NEU) Discordance.pptx
Implications
• Discordance rates highlight variability in receptor status between primary breast tumors and distant metastases across different sites.
• ER and PR discordance rates were significantly higher in bone and liver metastases compared to CNS metastases.
• HER2 discordance did not show statistically significant differences among the analyzed metastatic sites due to limited data availability.
Alterations in ER, PR, and HER2 following NACT vary widely.
• ER changes: 5–23%; PR changes: 14.5–67%.
• HER2 changes less frequently, loss more common than gain.
• Triple negative is most stable;
• ER/HER2-positive show highest change rates.
• Neoadjuvant endocrine therapy less common, PR changes up to 40%.
• Post-NACT ER or HER2 positive can initiate endocrine or anti-HER2 therapy,
but trial evidence is lacking.
Breast cancer :Receptor (ER/PR/HER2 NEU) Discordance.pptx
Breast cancer :Receptor (ER/PR/HER2 NEU) Discordance.pptx
Study/Trial ER Changes PR Changes
IMPACT Trial
More responders to anastrozole or tamoxifen with
higher baseline ER levels (p = 0.02)
Ellis et al.
No response of ER low expressors to tamoxifen;
some ER low tumors responded to letrozole
Small Study (23 patients)
Minimal to no change in ER status following
anastrozole treatment
Significant reduction in PR expression in 17/18
patients, 11 switched to PR−
National Nagasaki Medical Center
ER expression slightly reduced after NAET in 14.5% of
cases
PR expression loss in 40.1% of cases treated with
NAET vs. 8.2% with NACT
PALLET Trial
Non-significant changes in ER expression after 14
weeks of letrozole or letrozole + palbociclib
Significant reductions in PR expression (geomeans
PR: −96.4% vs. −94.9%)
PROACT Trial
5/40 anastrozole treated and 20/37 tamoxifen
treated tumors switched from ER+ to ER−
16/17 tumors switched from PR+ to PR− with
anastrozole; only 1/11 with tamoxifen
UK Retrospective Study (132 samples)
Only one tumor (0.7%) switched to ER− profile;
minimal changes in Allred score
Highly significant change in PR expression; 12.7%
switched from positive to negative
Category Details
Study Design
Retrospective analysis of breast cancer patients undergoing
neoadjuvant dual HER2-targeted therapy
Sample Size 163 female patients
HER2 Status Post-Therapy
- HER2 IHC 3+
36 patients; 12 remained IHC 3+, 9 evolved to IHC 2+ with
amplification, 9 evolved to IHC 2+ without amplification, 4 evolved
to IHC 1+, 2 evolved to IHC 0
- HER2 IHC 2+ with amplification
22 patients; 7 remained IHC 2+ with amplification, 4 evolved to IHC
3+, 4 evolved to IHC 2+ without amplification, 4 evolved to IHC 1+
without amplification, 2 evolved to IHC 1+ with amplification, 1
evolved to IHC 0
- HER2 NR with amplification
3 patients; 2 evolved to IHC 3+, 1 evolved to IHC 2+ without
amplification
Residual HER2 Status Breakdown 36 HER2-positive (59%), 24 HER2-low (36%), 3 HER2-ultralow (5%)
table focusing on the study design, sample size, and HER2 status after dual HER2-targeted therapy:
• Discordance in ER, PR, and HER2 status between primary and metastatic breast
cancer lesions is a significant clinical challenge.
• These changes influence treatment decisions and patient outcomes, necessitating
tailored therapeutic strategies.
• Conversion from ER/PR-positive to negative status is associated with reduced
responsiveness to endocrine therapies, impacting treatment efficacy and patient
survival.
• HER2-negative conversions limit the efficacy of HER2-targeted therapies, affecting
treatment outcomes adversely.
• Conversion from negative to positive ER/PR status correlates with improved overall
survival and treatment response.
• Conversely, conversion from positive to negative status may increase mortality risks
due to reduced treatment options and poorer prognosis.
• According to NCCN and ESMO guidelines, regular reassessment of ER, PR, and HER2
status is recommended at recurrence or progression to guide treatment decisions
effectively.
• Biomarker testing should be integrated into clinical practice to adapt therapies based
on updated receptor profiles and patient responses.
• Understanding the molecular mechanisms underlying receptor discordance is crucial
for refining treatment strategies and predicting therapeutic outcomes.
• Ongoing research aims to identify biomarkers and develop imaging techniques that
enhance the detection and monitoring of heterogeneous breast cancer subtypes.
• Incorporating advanced diagnostic tools and personalized medicine approaches is
essential for optimizing treatment outcomes and patient care in breast cancer.
• Continued collaboration between clinicians, researchers, and industry stakeholders is
needed to advance precision oncology and improve patient survival.
Breast cancer :Receptor (ER/PR/HER2 NEU) Discordance.pptx
• The ESR1 and PGR promoters undergo cyclic methylation and demethylation of
CpG dinucleotides, modulating ERα and PgR levels in HR+ breast cancer cells.
Methylation of the ESR1 promoter prevents transcription factors like AP2 from
binding, inhibiting ESR1 transcription. Zinc-finger E-box binding homeobox 1
(ZEB1) forms a complex with DNA methyltransferase (DNMT)3B and histone
deacetylase 1 (HDAC1) on the ESR1 promoter, leading to its hypermethylation.
Increased histone deacetylation further limits ESR1 transcription by condensing
nucleosome structure.
• The loss of ERα signaling also represses PGR transcription, involving polycomb
repressors, histone deacetylases, and PGR promoter methylation. Notably, three
methylation-sensitive sites in the PGR CpG islands are unmethylated in normal
breast tissue and PgR+ breast cancers but are hypermethylated in about 40% of
PgR- breast cancers. This hypermethylation is linked to a lack of PgR expression,
highlighting the role of epigenetic changes in hormone receptor loss and breast
cancer progression.
• The ESR1 gene on chromosome 6q25.1 encodes the estrogen receptor alpha
(ERα). ERα includes several domains: AF1, DNA-binding domain (DBD),
ligand-binding domain (LBD), AF2, and a flexible hinge domain. ERα binds
estrogens (E2), homodimerizes, and attaches to estrogen-responsive
elements (EREs) to activate gene transcription for cell growth and
proliferation.
• Genetic alterations in ESR1, such as mutations, deletions, insertions, and
loss of heterozygosity (LOH), can affect ERα function. While many alterations
do not cause loss of ERα expression, some, like homozygous deletions or
inactivating mutations, lead to functional loss and therapy resistance.
• The PGR gene on chromosome 11q22-23 encodes the progesterone
receptor (PgR) with isoforms A and B. PgR expression is regulated by ERα,
with PgR-A acting as a repressor and PgR-B as an activator. Genetic
alterations in PGR, including LOH, occur in 18-40% of ERα+ breast cancers
and often lead to loss of PgR expression.

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Breast cancer :Receptor (ER/PR/HER2 NEU) Discordance.pptx

  • 1. DR SUMIT KUMAR Assistant professor NEIGRIHMS, Shillong ? Mechanism ? After neoadjuvant chemotherapy ?After neoadjuvant endocrine therapy ?At the time of recurrence / metastasis ? After neoadjuvant her2 neu inhibitor
  • 2. Prevalence of ERα+ Breast Cancer: ERα+ breast cancer accounts for 75% of all breast cancer cases, with half also expressing PgR, forming HR-positive breast cancer. Function of Estrogen Receptors: ERα promotes cancer cell growth through activation of genomic and non-genomic pathways. ERβ can modulate ERα activity and counteract its effects. Hormone Receptor (HR) Status: HR status, determined by ERα and PgR expression, is a key prognostic and predictive factor in breast cancer. HER2/neu Receptor: HER2/neu is another critical receptor in breast cancer. Overexpression or amplification of HER2 is found in approximately 15-20% of breast cancers and is associated with aggressive disease. Significance of HR and HER2 Status: HR-positive breast cancer is associated with lower proliferation rates, longer disease-free survival (DFS), and overall survival (OS). HER2-positive cancers benefit from targeted therapies but are generally more aggressive.
  • 3. Endocrine Therapy (ET): ETs, such as tamoxifen, fulvestrant, and aromatase inhibitors, target ERα signaling and are standard treatments for HR+ breast cancer. HER2-Targeted Therapies: HER2-positive cancers are treated with targeted therapies like trastuzumab and pertuzumab, which specifically inhibit HER2 signaling. Receptor Discordance: Changes in receptor status (e.g., from HR+ to HR− or HER2− to HER2+) can occur during disease progression, impacting treatment decisions. Mechanisms of Discordance: Receptor discordance can result from genetic mutations, epigenetic modifications, and selective pressure from treatments. Clinical Impact of Discordance: Regular reassessment of receptor status is essential to guide therapy adjustments and improve patient outcomes, emphasizing the importance of advanced molecular profiling to tailor personalized treatment strategies.
  • 7. • Encodes Estrogen Receptor Alpha (ERα). • Domains: AF1, DNA-binding (DBD), Ligand-binding (LBD), AF2, Hinge. • Binds estrogens (E2), homodimerizes, and attaches to estrogen-responsive elements (EREs) to activate gene transcription. Genetic Alterations: • Mutations, deletions, insertions, loss of heterozygosity (LOH). • Can lead to functional loss and therapy resistance. •Encodes Progesterone Receptor (PgR) with isoforms A and B. •PgR expression is regulated by ERα. • PgR-A: Repressor • PgR-B: Activator Genetic Alterations: • LOH occurs in 18-40% of ERα+ breast cancers. • Often leads to loss of PgR expression
  • 8. • Modulation: Cyclic methylation/demethylation controls ERα levels. • Inhibition: Methylation blocks transcription factors like AP2, preventing ESR1 transcription. • Complex Formation: ZEB1 with DNMT3B and HDAC1 induces hypermethylation and histone deacetylation, tightening chromatin and reducing transcription. •Repression: Loss of ERα signaling decreases PGR transcription. •Mechanism: Involves polycomb repressors, histone deacetylases, and promoter methylation. •Impact: Hyper-methylation at key sites occurs in ~40% of PgR- breast cancers, leading to loss of PgR expression. Epigenetics involves changes in gene expression without altering the DNA sequence, primarily through mechanisms like DNA methylation and histone modification, which regulate how genes are turned on or off. These epigenetic changes contribute to hormone receptor loss and breast cancer progression.
  • 9. • Growth factor signaling involves proteins (growth factors) that bind to receptors on the cell surface, triggering a cascade of intracellular events that promote cell growth, proliferation, and survival. • The PI3K/AKT/mTORC1 and MAPK signaling pathways negatively correlate with ERα expression. Loss of PTEN, an inhibitor of PI3K/AKT/mTORC1, is linked to the loss of ERα and PgR in breast cancer. • Around 30-40% of sporadic breast cancers show PTEN loss of heterozygosity (LOH), associated with higher tumor grades and PgR loss. with growth factors like IGF-I, EGF, and heregulin downregulates PGR mRNA and PgR protein in cell lines. result in MAPK hyperactivation and ERα downregulation. HER2+ breast cancers express lower ERα levels and show resistance to endocrine therapies without HER2 inhibition due to HER2-mediated signaling through PI3K/AKT/mTORC1 and MAPK pathways. leads to lower ESR1 gene expression in ERα+ PgR− cell lines, but inhibition of this pathway can restore ERα expression, demonstrating its reversible nature. • NFkB, often constitutively active in ERα− breast cancers, correlates with lower ERα levels. Its activation, possibly due to MAPK hyperactivation or PI3K/AKT/mTORC1 signaling, further contributes to ERα downregulation.
  • 10. • ESR1 mRNA is 4.3 kb long and contains a 3' untranslated region (UTR) with AU-rich sequences that promote mRNA degradation. • Changes in ESR1 mRNA structure can impact the translation of ERα, though the exact mechanisms are still being studied. • MicroRNAs (miRNAs) are small RNA molecules that regulate gene expression. For instance: • miR-222/221 targets ESR1 mRNA, leading to its degradation. Levels of these miRNAs are higher in ERα− breast cancer cells compared to ERα+ cells. • miR-206 and miR-92 also influence ERα and ERβ levels by binding to their respective mRNA 3' UTRs. • miR-27a targets ZBTB10, a protein involved in directly regulating ERα expression in HR+ breast cancer cell lines. • These miRNAs play a crucial role in fine-tuning ERα expression post- transcriptionally, contributing to the complex regulation of hormone receptor levels in breast cancer.
  • 11. : • ERα undergoes polyubiquitination and subsequent degradation via the ubiquitin proteasome system (UPS) when bound to estradiol (E2). • This process is mediated by E2-ERα complex binding to estrogen responsive elements (EREs), recruiting E3-ubiquitin ligases. • Selective estrogen receptor degraders (SERDs) like fulvestrant exploit ERα polyubiquitination for therapeutic benefit in HR+/HER2− breast cancer. Phosphorylation at specific residues modulates ERα ubiquitination: • SRC-induced phosphorylation at Y537 residue promotes ERα ubiquitination and degradation. • Phosphorylation by GSK3, LMTK3, and ABL stabilizes ERα and enhances its transcriptional activity.
  • 12. : • MUC1 stabilizes ERα binding to ERE promoters, enhancing ERα-induced gene transcription; its knockdown reduces ERα levels in HR+ breast cancer cells. • PIN1 inhibits ERα degradation by preventing E3 ligase interaction. • RB protein interacts with ERα to regulate its stability; RB loss correlates with reduced ERα levels in breast cancer cells. • HSP90 and p23 chaperones protect ERα from UPS-mediated degradation. • RNF31 mediates ERα monoubiquitination, stabilizing ERα and enhancing its activity. • Palmitoylation stabilizes ERα and promotes its localization to the cell membrane, activating oncogenic signaling. These diverse post-translational modifications and interactions finely regulate ERα levels and activity in breast cancer, impacting response to hormonal therapies and disease progression.
  • 13. Hypoxia in tumors results from rapid growth and poor vascularization. • It promotes tumor cell growth, alters metabolism, and facilitates metastasis. • Impact on ERα Expression: • In HR+ breast cancer: • Hypoxia reduces ERα protein levels by promoting its degradation via the proteasome. • HIF-1α, a key regulator in hypoxia, may inhibit ESR1 gene transcription, contributing to decreased ERα levels (Figure 1). Research Challenges and Perspectives: • The relationship between HIF-1α signaling and ERα expression needs further clarification. • Understanding hypoxia's influence on ERα sheds light on its role in breast cancer progression and resistance to therapies.
  • 14. • BRCA1 interacts with RNA polymerase II. • Activates ESR1 gene transcription by binding to its promoter and recruiting Oct1. • Loss of BRCA1 function leads to reduced ERα protein levels. • Despite ERα-positive status, tumors may exhibit lower ERα expression due to impaired transcriptional activation by BRCA1. • BRCA1 promotes PgR protein degradation via ubiquitination. • Induces chromatin silencing at PgR-regulated promoters through the BRCA1/BARD1 complex. • BRCA gene mutations disrupt normal transcriptional regulation of hormone receptors. • Resultant hormone receptor discordance impacts treatment response and tumor behavior.
  • 15. • Definition: Accumulation of genetic mutations over time leading to the emergence of distinct tumor cell subclones. • Impact: Results in variability in hormone receptor expression (e.g., ERα, PgR) among tumor cells within the same lesion. • Changes: Alterations in DNA methylation and histone modifications. • Effect: Influence gene expression patterns, contributing to phenotypic diversity including hormone receptor status. • Factors: Variations in oxygen levels (hypoxia), nutrient availability, and pH within the tumor microenvironment. • Contribution: Influence cellular behavior, survival, and adaptation of different tumor cell populations. • Presence: Subpopulations of CSCs with self-renewal and differentiation capabilities. • Role: Contribute to intratumoral heterogeneity by giving rise to diverse progeny with varying hormone receptor expression. • Spatial Variability: Uneven distribution of tumor cells with different molecular profiles within the tumor mass. • Temporal Changes: Dynamic alterations in molecular features over the course of tumor progression and treatment.
  • 16. • The transition from HR negative to positive status in breast cancer management can occur through several mechanisms, although it is generally less common than the opposite scenario (HR positive to negative). • some mechanisms that can contribute to this phenomenon: Definition: Breast tumors are composed of heterogeneous cell populations. During treatment, some HR-positive cells may survive while HR-negative cells are eliminated. Mechanism: Chemotherapy or endocrine therapy can exert selective pressure on tumor cells. HR-positive cells, which may have inherent or acquired resistance mechanisms, survive treatment while HR-negative cells are eradicated. Changes: Alterations in DNA methylation patterns or histone modifications. Effect: These epigenetic modifications can potentially lead to reactivation of HR genes (ESR1 for ERα or PGR for PgR), thereby switching the phenotype from HR-negative to HR-positive. Endocrine Therapy: Treatment with hormonal therapies (e.g., tamoxifen, aromatase inhibitors) can alter the hormonal environment within the tumor. Effect: This can influence the expression and activity of hormone receptors in surviving tumor cells, potentially leading to a change in HR status from negative to positive.
  • 17. Stromal Influences: Changes in the tumor microenvironment, such as interactions with immune cells or fibroblasts, can impact tumor cell phenotype. Induction: Certain signals within the microenvironment may induce or suppress the expression of hormone receptors in tumor cells. Acquisition of Mutations: Rarely, genetic mutations or alterations may occur during treatment that lead to activation of HR genes in previously HR-negative cells. Selective Advantage: Cells with these mutations may gain a growth advantage under the selective pressure of therapy. Diverse Cell Populations: Tumors are composed of heterogeneous cell populations with varying molecular characteristics. Survival of Subpopulations: HR-positive cells may exist as minor subpopulations within a predominantly HR-negative tumor mass. Treatment can selectively eliminate HR-negative cells, allowing HR-positive cells to proliferate and dominate the residual tumor. Summary: Transition from HR-negative to HR-positive status during breast cancer management is a complex process involving clonal selection, epigenetic changes, hormonal environment alterations, interactions with the tumor microenvironment, genetic mutations, and intra-tumor heterogeneity. While less common than the reverse transition, understanding these mechanisms can inform strategies for monitoring and managing breast cancer, particularly in cases where HR status conversion impacts treatment decisions.
  • 18. Data Details Prognostic Impact of HR Loss Conversion from ERα+ to ERα- status associated with a 48% increase in risk of death compared to stable ERα+ status (HR = 1.48, 95% CI 1.08-2.05). PgR Loss and Clinical Behaviour Loss of PgR in tumors with high ERα associated with more aggressive behavior and resistance to SERMs. Discordance Between Diagnostic and Surgical Samples Low discordance rates: ERα 1.8%, PgR 15% between core needle biopsy (CNB) and surgical samples in early-stage breast cancer. Discordance in Lymph Node Metastases Rare discordance: ERα between primary tumors and axillary lymph node metastases (2/50, 4%). Technical Challenges in HR Assessment Variability due to sampling methods (CNB vs. surgical resection), delays in fixation, and IHC staining reproducibility. Standardization of HR Assessment Improved reliability in determining ERα and PgR status with standardized IHC techniques. Impact of Decalcification on HR Assessment Potential alteration of HR expression in bone metastases due to decalcification of biopsy samples.
  • 19. • Hormone Receptor (HR) status, including ER and PgR, is crucial in guiding breast cancer treatment. • HR status can change between primary and recurrent/metastatic tumors. • Reassessment of HR status is important to tailor treatment plans and improve patient outcomes. • HR discordance rates between primary and recurrent/metastatic breast cancer: • ER status conversion: 14-24% • PgR status conversion: 33% • Discordance can involve conversion from HR+ to HR- or from HR- to HR+.
  • 20. • HR status should be reassessed at the first recurrence or progression. • Regular reassessment is recommended during subsequent progressions if clinically indicated. • Endocrine Therapy: • Tamoxifen and aromatase inhibitors can lead to changes in ER and PgR expression. • Neoadjuvant endocrine therapy may reduce ERα and PgR levels. • Chemotherapy: • Anthracyclines and taxanes have been associated with reductions in PgR expression and changes in ER levels. • Chemotherapy-induced epigenetic modifications may lead to HR status changes.
  • 21. • Recommend biopsy of at least one metastatic site to reassess HR and HER2 status at first recurrence or progression. • Suggest reevaluating ER, PgR, and HER2 status at recurrence or metastasis. • Recommend mandatory reassessment of HR and HER2 status in metastatic disease. • Practical Considerations • Use validated IHC techniques for HR testing. • Ensure proper tissue handling and fixation. • A multidisciplinary approach is essential for accurate interpretation and treatment planning.
  • 23. HER2 Status in Breast Cancer: HER2 status is crucial for determining treatment strategies and prognosis in breast cancer. Definition of HER2 Discordance: Change in HER2 status between primary and recurrent/metastatic tumors. • Positive to Negative: Loss of HER2 expression in recurrent/metastatic tumors previously HER2-positive. • Negative to Positive: Gain of HER2 expression in recurrent/metastatic tumors previously HER2-negative. Importance of Discordance • Impact on Treatment: Changes in HER2 status can lead to different therapeutic approaches. • Prognostic Value: Discordance can influence patient outcomes and guide clinical decisions.
  • 24. Primary mechanisms that can lead to changes in HER2 status from positive to negative and vice versa Mechanism Positive to Negative HER2 Neu Negative to Positive HER2 Neu Tumor Heterogeneity Loss of HER2 expression in some tumor regions leading to overall negative status Gain of HER2 expression in previously HER2-negative regions Clonal Evolution Treatment pressure selecting for clones without HER2 amplification Emergence of new clones with HER2 amplification Epigenetic Changes DNA methylation silencing HER2 gene expression Epigenetic reprogramming leading to HER2 gene expression Technical Factors Variability in biopsy sampling, testing techniques, and tissue handling leading to misclassification Initial false-negative result corrected upon retesting Genetic Instability Mutations leading to loss of HER2 gene or its expression New mutations activating HER2 gene Treatment-Induced Changes Anti-HER2 therapies causing downregulation or loss of HER2 expression Other treatments reducing competition, allowing HER2-expressing cells to proliferate Environmental Factors Changes in tumor microenvironment inhibiting HER2 expression Changes in microenvironment favoring HER2 expression Loss of HER2 Gene Genetic deletion or loss of the HER2 gene Genetic amplification of the HER2 gene
  • 25. : Reduction in HER2 protein expression while retaining ERBB2 gene amplification. • Induction by Anti-HER2 Agents: Drugs like trastuzumab cause HER2 internalization and downregulation at the membrane level. 1. Untreated HER2-Positive Tumors: • HER2 gene amplification increases receptor expression. • Promotes dimerization and activation of MAPK and PI3K/AKT/mTOR pathways. 2. Immune Cell Role: • HER2 downregulation observed with trastuzumab when immune cells are involved. • Interferon gamma (IFN-γ) from immune cells activates STAT1, leading to HER2 downregulation. 3. Combination Therapies: • Trastuzumab and pertuzumab dual blockade increases HER2 downregulation. • ADCs like trastuzumab emtansine (T-DM1) also induce downregulation, possibly leading to resistance. 4. Tyrosine Kinase Inhibitors (TKIs): • TKIs prevent HER2 internalization, increasing surface HER2 expression. • Combining TKIs with anti-HER2 antibodies enhances antitumor activity.
  • 26. ? • Definition: Variability in HER2 expression within different areas of the same tumor. 2009: HER2 heterogeneity defined as 5%-50% tumor cells with: • Ratio ≥ 2.2 (dual probes) or ≥ 6 HER2 signals/cell (single probes). 2013 Update: Adjusted cut-off to 10% and ratio to 2.0. 1.Filho et al. (2018): • Evaluated 164 patients treated with T-DM1 and pertuzumab. • Found 10% of samples were heterogeneous. • Heterogeneous tumors had no complete response to treatment, while 55% of non- heterogeneous tumors did. • Most heterogeneous cases were IHC 2+ and ER-positive. 2.Caswell-Jin et al. (2019): • Used whole-exome sequencing before and after treatment. • Found new mutations in post-treatment samples, not present before treatment. • Indicates resistant cells were selected by the treatment.
  • 27. : HER2-Enriched (HER2-E) to Luminal A after neoadjuvant treatment Cause: Decreased expression of cell proliferation genes post-treatment exposure • Initially utilized microarray analysis (400+ genes) • Currently employs PAM50 classifier for tumor subtyping : 1. Neoadjuvant Treatment Studies: • Significant subtype switch observed in many patients across different drug regimens • HER2-E tumors frequently switch to Luminal A 2. Brasó-Maristany et al.: • Subtype switch can be reversible after stopping anti-HER2 therapy 3. Pernas et al.: • In a cohort of 26 patients with residual disease post-treatment: • 81.8% HER2-E tumors switched to non-HER2-E subtypes • 7 out of 26 patients converted to HER2-negative status
  • 29. Available online 21 November 2013
  • 30. : • Heterogeneity: I2 = 79%, p < 0.0001 • Primary vs. Distant Metastases: 41 (95% CI: 37–45) • Primary vs. Loco-regional Relapse: 26 (95% CI: 21–32) • Heterogeneity: I2 = 77%, p < 0.0001 • Primary vs. Distant Metastases: 10 (95% CI: 7–14) • Primary vs. Loco-regional Relapse: 6 (95% CI: 3–9) • IHC and FISH: 10 (95% CI: 7–12) • IHC Only: 5 (95% CI: 2–8) • Total Studies: 48 • Total Patients: 9926
  • 32. Implications • Discordance rates highlight variability in receptor status between primary breast tumors and distant metastases across different sites. • ER and PR discordance rates were significantly higher in bone and liver metastases compared to CNS metastases. • HER2 discordance did not show statistically significant differences among the analyzed metastatic sites due to limited data availability.
  • 33. Alterations in ER, PR, and HER2 following NACT vary widely. • ER changes: 5–23%; PR changes: 14.5–67%. • HER2 changes less frequently, loss more common than gain. • Triple negative is most stable; • ER/HER2-positive show highest change rates. • Neoadjuvant endocrine therapy less common, PR changes up to 40%. • Post-NACT ER or HER2 positive can initiate endocrine or anti-HER2 therapy, but trial evidence is lacking.
  • 36. Study/Trial ER Changes PR Changes IMPACT Trial More responders to anastrozole or tamoxifen with higher baseline ER levels (p = 0.02) Ellis et al. No response of ER low expressors to tamoxifen; some ER low tumors responded to letrozole Small Study (23 patients) Minimal to no change in ER status following anastrozole treatment Significant reduction in PR expression in 17/18 patients, 11 switched to PR− National Nagasaki Medical Center ER expression slightly reduced after NAET in 14.5% of cases PR expression loss in 40.1% of cases treated with NAET vs. 8.2% with NACT PALLET Trial Non-significant changes in ER expression after 14 weeks of letrozole or letrozole + palbociclib Significant reductions in PR expression (geomeans PR: −96.4% vs. −94.9%) PROACT Trial 5/40 anastrozole treated and 20/37 tamoxifen treated tumors switched from ER+ to ER− 16/17 tumors switched from PR+ to PR− with anastrozole; only 1/11 with tamoxifen UK Retrospective Study (132 samples) Only one tumor (0.7%) switched to ER− profile; minimal changes in Allred score Highly significant change in PR expression; 12.7% switched from positive to negative
  • 37. Category Details Study Design Retrospective analysis of breast cancer patients undergoing neoadjuvant dual HER2-targeted therapy Sample Size 163 female patients HER2 Status Post-Therapy - HER2 IHC 3+ 36 patients; 12 remained IHC 3+, 9 evolved to IHC 2+ with amplification, 9 evolved to IHC 2+ without amplification, 4 evolved to IHC 1+, 2 evolved to IHC 0 - HER2 IHC 2+ with amplification 22 patients; 7 remained IHC 2+ with amplification, 4 evolved to IHC 3+, 4 evolved to IHC 2+ without amplification, 4 evolved to IHC 1+ without amplification, 2 evolved to IHC 1+ with amplification, 1 evolved to IHC 0 - HER2 NR with amplification 3 patients; 2 evolved to IHC 3+, 1 evolved to IHC 2+ without amplification Residual HER2 Status Breakdown 36 HER2-positive (59%), 24 HER2-low (36%), 3 HER2-ultralow (5%) table focusing on the study design, sample size, and HER2 status after dual HER2-targeted therapy:
  • 38. • Discordance in ER, PR, and HER2 status between primary and metastatic breast cancer lesions is a significant clinical challenge. • These changes influence treatment decisions and patient outcomes, necessitating tailored therapeutic strategies. • Conversion from ER/PR-positive to negative status is associated with reduced responsiveness to endocrine therapies, impacting treatment efficacy and patient survival. • HER2-negative conversions limit the efficacy of HER2-targeted therapies, affecting treatment outcomes adversely. • Conversion from negative to positive ER/PR status correlates with improved overall survival and treatment response. • Conversely, conversion from positive to negative status may increase mortality risks due to reduced treatment options and poorer prognosis.
  • 39. • According to NCCN and ESMO guidelines, regular reassessment of ER, PR, and HER2 status is recommended at recurrence or progression to guide treatment decisions effectively. • Biomarker testing should be integrated into clinical practice to adapt therapies based on updated receptor profiles and patient responses. • Understanding the molecular mechanisms underlying receptor discordance is crucial for refining treatment strategies and predicting therapeutic outcomes. • Ongoing research aims to identify biomarkers and develop imaging techniques that enhance the detection and monitoring of heterogeneous breast cancer subtypes. • Incorporating advanced diagnostic tools and personalized medicine approaches is essential for optimizing treatment outcomes and patient care in breast cancer. • Continued collaboration between clinicians, researchers, and industry stakeholders is needed to advance precision oncology and improve patient survival.
  • 41. • The ESR1 and PGR promoters undergo cyclic methylation and demethylation of CpG dinucleotides, modulating ERα and PgR levels in HR+ breast cancer cells. Methylation of the ESR1 promoter prevents transcription factors like AP2 from binding, inhibiting ESR1 transcription. Zinc-finger E-box binding homeobox 1 (ZEB1) forms a complex with DNA methyltransferase (DNMT)3B and histone deacetylase 1 (HDAC1) on the ESR1 promoter, leading to its hypermethylation. Increased histone deacetylation further limits ESR1 transcription by condensing nucleosome structure. • The loss of ERα signaling also represses PGR transcription, involving polycomb repressors, histone deacetylases, and PGR promoter methylation. Notably, three methylation-sensitive sites in the PGR CpG islands are unmethylated in normal breast tissue and PgR+ breast cancers but are hypermethylated in about 40% of PgR- breast cancers. This hypermethylation is linked to a lack of PgR expression, highlighting the role of epigenetic changes in hormone receptor loss and breast cancer progression.
  • 42. • The ESR1 gene on chromosome 6q25.1 encodes the estrogen receptor alpha (ERα). ERα includes several domains: AF1, DNA-binding domain (DBD), ligand-binding domain (LBD), AF2, and a flexible hinge domain. ERα binds estrogens (E2), homodimerizes, and attaches to estrogen-responsive elements (EREs) to activate gene transcription for cell growth and proliferation. • Genetic alterations in ESR1, such as mutations, deletions, insertions, and loss of heterozygosity (LOH), can affect ERα function. While many alterations do not cause loss of ERα expression, some, like homozygous deletions or inactivating mutations, lead to functional loss and therapy resistance. • The PGR gene on chromosome 11q22-23 encodes the progesterone receptor (PgR) with isoforms A and B. PgR expression is regulated by ERα, with PgR-A acting as a repressor and PgR-B as an activator. Genetic alterations in PGR, including LOH, occur in 18-40% of ERα+ breast cancers and often lead to loss of PgR expression.