Fatty acids and breast cancer
Dr Nina Bailey
BSc MSc PhD ANutr
Common cancers (males vs females) UK, 2010

25%

31%

47%

46%
14%

Prostate

Breast

12%

Lung

14%

Bowel
Other sites

h...
 Breast cancer is one of the most commonly diagnosed cancers and the
leading cause of death from cancer among women,

 B...
Diet and lifestyle
 For the past few decades, epidemiological studies have suggested
that a healthy diet and lifestyle is...
Dietary fat
 Dietary fat is thought to be one of the main risk factors, on the basis of reports
of positive correlations ...
•
•
•
•

Cell fluidity
Metabolism
Growth and development
Brain structure and function

• Eicosanoid production
 Immunity
...
AA, EPA and the cell cycle
 A high rate of cell proliferation rate and a low rate of apoptosis are
the hallmark of abnorm...
A new biomarker in cancer patients: the AA to EPA ratio
 Aim To evaluate the potential value of tumour risk assessment in...
Cancer – an inflammatory disease?
 The link between non-resolving inflammation and cancer is well
documented, with epidem...
Inflammatory response

Resoleomics - the process of inflammation resolution

Eicosanoid switch

Stop signal

Pro-inflammat...
Inflammation and omega-3 & omega-6 fatty acid intake among
breast cancer survivors
The Health, Eating, Activity and Lifest...
Inflammation and tumour development
 Inflammation causes cellular stress and may trigger DNA damage or
genetic instabilit...
Phospholipid
Phospholipase A2
Arachidonic acid

COX-1

COX-2

PGH2

PGD2 PGE2 PGF2

PGI2
The role of COX
 Before the discovery of COX-2 it was known that prostaglandin synthesis
could be stimulated by a variety...
Arachidonic acid

COX-1

COX-2

Constitutive
‘gate-keeping functions’

Induced

Homeostatic function
Gastrointestinal trac...
COX-2 over-expression plays an important role in the pathogenesis of
malignant breast cancer in humans
COX-2 plays a key r...
COX-2 expression in aggressive breast cancer
HER-2 (human epidermal growth factor 2)
 Over-expression (HER-2/neu-positive...
COX-2 expression and breast cancer prognosis
 Cancer group: 57 primary breast cancer patients
Control group: 27 patients ...
COX-2, aromatase and oestrogen
 About 75% of breast cancers are ER positive
 Oestrogens are produced from androgens by t...
Arachidonic acid

COX-1

COX-2

Constitutive
‘gate-keeping functions’

Induced

Homeostatic function
Gastrointestinal trac...
Women’s Health Initiative (WHI) Observational Study designed to address
some of the major causes of morbidity and mortalit...
Data from 91 epidemiological studies examined the dose response of relative
risk and level of NSAID intake for ten human m...
Use of COX-2 inhibitors and breast cancer risk
Meta-analysis of 6 cohort studies (number of cases ranged from 14 to 2414) ...
Use of COX-2 inhibitors and breast cancer risk
Meta-analysis of 26 studies with 528,705 participants
(Zhao et al., 2009)
•...
COX-2

Aromatase

Prostaglandin

COX-2 inhibitor

Angiogenesis

Oestrogen
Facilitation of tumour growth

Oestrogen dependa...
Selective vs non-selective NSAIDS
 Non-selective NSAIDs block both COX-1 and COX-2 [aspirin, ibuprofen
(Brufen, Nurofen),...
Selective COX-2 inhibitor drugs still have side effects
 Merck & Co withdraws Rofecoxib (Vioxx, Vioxxacute) in September ...
Arachidonic acid

EPA

COX-1

COX-2

Constitutive
‘gate-keeping functions’

Induced

Homeostatic function
Gastrointestinal...
The role of EPA as a competitive inhibitor
High arachidonic acid
levels

COX-2

Pro-inflammatory ‘cancer
driving’ prostagl...
Intake of fish and marine n-3 polyunsaturated fatty acids and risk of breast
cancer: meta-analysis of data from 21 indepen...
Intake of fish and marine n-3 polyunsaturated fatty acids and risk of breast
cancer: meta-analysis of data from 21 indepen...
Fish consumption patterns
•
•
•
•
•

Type (oily vs white; farmed vs wild)
Omega-3 content/omega-6 content
EPA to DHA ratio...
Dietary polyunsaturated fatty acids and breast cancer risk in Chinese women:
a prospective cohort study (Shanghai Women’s ...
Specialty supplements and breast cancer risk in the VITamins And Lifestyle
(VITAL) Cohort
 Postmenopausal women (n = 35,0...
•

Dietary intake of specific fatty acids and breast cancer risk among postmenopausal
women in the VITAL cohort

 Associa...
Modulating eicosanoids
 Products (eicosanoids) derived from AA and EPA play a central role in
inflammation and tissue hom...
Modulation of angiogenesis by AA and EPA
The formation of new blood vessels (angiogenesis), a critical process that affect...
BRCA (breast cancer susceptibility protein) genes
 BRCA1 and BRCA2 are human genes that belong to a class of genes
known ...
Omega fatty acids and BRCA genes
 EPA in vitro has been shown to mediate gene expression in human cells
 AA down-regulat...
Arachidonic acid and eicosapentaenoic acid metabolism contribute to cancer
risk and progression through pro-and anti-infla...
EPA and cancer cachexia
 Cachexia is a form of muscle wasting often associated with advanced stage
cancer
 Inflammatory ...
GLA and breast cancer
 GLA is metabolised to DGLA to produce anti-inflammatory eicosanoids
 Addition of GLA to EPA reduc...
EPA and breast cancer
 EPA displaces AA and reduces the production of inflammatory products


EPA blocks the activity of...
AA and breast cancer



AA gives rise to key pro-inflammatory mediators involved in orchestrating
cross-talk between tum...
Shifting the balance
 AA and EPA content of cell membranes can be altered through
consumption of omega-3 EPA (marine prod...
ninab@igennus.com
www.igennus.com
drninabailey.co.uk
01223 421434
RBC content of EPA (%)

The effect of EPA supplementation on red blood cell (RBC)
membranes EPA content

Maki & Rains, 201...
Fatty acid levels ( g/g)

Changes in erythrocyte membrane omega-3 fatty acid levels
following 12 weeks treatment with 1g e...
References
•
•
•
•
•
•
•

•

•
•
•

Alfano, C. M., I. Imayama, et al. (2012). "Fatigue, inflammation, and omega-3 and omeg...
References
•
•

•
•
•
•
•
•
•

•
•

Harris, R. E., R. T. Chlebowski, et al. (2003). "Breast cancer and nonsteroidal anti-i...
References
•
•
•

•
•
•
•
•
•
•

•
•

Rose, D. P. (1997). "Dietary Fat, Fatty Acids and Breast Cancer." Breast cancer 4(1)...
References
•
•

Zheng, J. S., X. J. Hu, et al. (2013). "Intake of fish and marine n-3 polyunsaturated fatty acids and risk...
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Modulating Breast Cancer Risk: The AA:EPA Ratio - webinar - Igennus

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Breast cancer is the leading cause of death from cancer among women, accounting for 23% of the total cancer cases and 14% of cancer deaths in 2008. As dietary fat is thought to be one of the main risk factors, this webinar will focus on the opposing effects of the omega-6 fatty acid arachidonic acid (AA) and the omega-3 fatty acid eicosapentaenoic acid (EPA) on factors related to breast cancer risk, development and prognosis, including their influence on cyclooxygenase activity and prostaglandin production, the impact of inflammation within the tissue microenvironment, impact on aromatase and oestrogen production and impact on genetic aspects of breast cancer such as modulation of BRAC1 and BRAC2 genes.

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  • 2008
  • 2008
  • Not pancreatic, urinary bladder, or renal cancer
  • Not pancreatic, urinary bladder, or renal cancer
  • Not pancreatic, urinary bladder, or renal cancer
  • Adjusted for age, body mass index, total energy, family history of breast cancer, alcohol use, tobacco use, education, use of hormone replacementtherapy, personal history of diabetes, menopausal status, age at menopause, age at menarche, parity, age at first pregnancy, level of physical activity,red meat intake, fish intake and vitamin E intake.
  • residents of western Washington State
  • Modulating Breast Cancer Risk: The AA:EPA Ratio - webinar - Igennus

    1. 1. Fatty acids and breast cancer Dr Nina Bailey BSc MSc PhD ANutr
    2. 2. Common cancers (males vs females) UK, 2010 25% 31% 47% 46% 14% Prostate Breast 12% Lung 14% Bowel Other sites http://www.cancerresearchuk.org/cancer-info/cancerstats/incidence/commoncancers 11% Lung Bowel Other sites
    3. 3.  Breast cancer is one of the most commonly diagnosed cancers and the leading cause of death from cancer among women,  Breast cancer accounted for 31% of the total cancer cases in 2010  Risk factors: Gender Hormones Aging Reproductive history HRT/birth control Breast density Genetic risk factors Family history Alcohol consumption Obesity Sedentary lifestyle Dietary factors
    4. 4. Diet and lifestyle  For the past few decades, epidemiological studies have suggested that a healthy diet and lifestyle is critical for the prevention of breast cancer  For women living in low-risk countries, the risk of developing breast cancer increases upon immigration to a high-risk country (exposure to Western lifestyle), which suggests that this cancer is influenced by modifiable lifestyle or environmental factors (Ziegler et al., 1993)  Dietary fat is one of the most intensively studied dietary factors closely related with risk
    5. 5. Dietary fat  Dietary fat is thought to be one of the main risk factors, on the basis of reports of positive correlations between dietary fat intake and increased risks for cancers of the breast, colon and prostate  Epidemiological and in particular experimental studies have shown the link between dietary fat and breast cancer (Rose 1997)  The effect of a high fat diet on the risk of breast cancer may not be as important as the effect of the different kinds of dietary fat, including saturated, monounsaturated and polyunsaturated fat  Evidence suggests that the polyunsaturated fatty acids affect breast cancer proliferation, differentiation and prognosis  The omega-6 to omega-3 ratio
    6. 6. • • • • Cell fluidity Metabolism Growth and development Brain structure and function • Eicosanoid production  Immunity  Cardiovascular health  Inflammation • Cell cycle control
    7. 7. AA, EPA and the cell cycle  A high rate of cell proliferation rate and a low rate of apoptosis are the hallmark of abnormal cell growth  AA and EPA have opposing effects on the proliferation, differentiation and apoptosis of genetically altered cells and therefore the disposal/accumulation of DNA damaged tissue (Cathcart et al, 2011)  The antiproliferative effects of EPA combined with the ability to induce programmed cell death suggests that E-EPA supplementation may have a significant impact on halting disease progression (Hawcroft et al., 2010; Hawcroft et al., 2012)
    8. 8. A new biomarker in cancer patients: the AA to EPA ratio  Aim To evaluate the potential value of tumour risk assessment in colon and breast cancer patients by determining the AA to EPA ratio in plasma in a case-control study against healthy patients (Garassino et al., 2006)  Findings Colorectal cancer AA/EPA ratio was 22.232+1.852 compared to 14.25+1.083 for healthy subjects (median age 70; range 53 - 81) Breast cancer The AA/EPA ratio was 21.029+2.584 compared to 12.10+1.414 in healthy subjects (median age 77; range 44 - 86)
    9. 9. Cancer – an inflammatory disease?  The link between non-resolving inflammation and cancer is well documented, with epidemiological evidence supporting that approximately 25% of all human cancer worldwide is caused by non-resolving inflammation  Inflammatory cells are found in the microenvironment of most, if not all tumours  High AA content of cells indicates a pro-inflammatory microenvironment  Products derived from inflammatory cells influence almost every aspect of cancer Vendramini-Costa & Carvalho 2012
    10. 10. Inflammatory response Resoleomics - the process of inflammation resolution Eicosanoid switch Stop signal Pro-inflammatory reduced LTB4 PGE2 Anti-inflammatory increased Time Initiation Resolution Bosma-den Boer et al., 2013 Termination
    11. 11. Inflammation and omega-3 & omega-6 fatty acid intake among breast cancer survivors The Health, Eating, Activity and Lifestyle Study (HEAL) Investigated the correlation between inflammation and fatigue and the intake of omega-6 and omega-3 PUFAs among breast cancer survivors  Six hundred thirty-three particiants (mean age, 56 years; stage I to IIIA)  Higher intake of omega-6 relative to omega-3 PUFAs was associated with higher levels of the inflammatory marker C-reactive protein  Survivors with the highest C-reactive protein had the highest levels of fatigue Alfano et al., 2012
    12. 12. Inflammation and tumour development  Inflammation causes cellular stress and may trigger DNA damage or genetic instability  Chronic inflammation may contribute to primary genetic mutations leading to malignant cell transformation  Inflammation has an important role in all phases of tumour development: • Initiation • Promotion • Invasion • Metastatic dissemination  Thus, suppression of pro-inflammatory pathways may provide opportunities for both prevention and treatment of cancer
    13. 13. Phospholipid Phospholipase A2 Arachidonic acid COX-1 COX-2 PGH2 PGD2 PGE2 PGF2 PGI2
    14. 14. The role of COX  Before the discovery of COX-2 it was known that prostaglandin synthesis could be stimulated by a variety of substances including cytokines, growth factor and tumour promoters  These effects were due to activation of phospholipases which supply arachidonic acid to COX  The two COX enzymes are regulated independently: COX-1 is constitutively expressed COX-2 is inducible and expressed only in response to certain stimuli  COX-2 is over-expressed in cancer
    15. 15. Arachidonic acid COX-1 COX-2 Constitutive ‘gate-keeping functions’ Induced Homeostatic function Gastrointestinal tract Renal tract Platelet function Macrophage differentiation Inflammation
    16. 16. COX-2 over-expression plays an important role in the pathogenesis of malignant breast cancer in humans COX-2 plays a key role in tumourigenesis through • • • • • • stimulating epithelial cell proliferation inhibiting apoptosis stimulating angiogenesis enhancing cell invasiveness mediating immune suppression increasing the production of mutagens Singh-Ranger et al., 2002
    17. 17. COX-2 expression in aggressive breast cancer HER-2 (human epidermal growth factor 2)  Over-expression (HER-2/neu-positive) of this gene has been shown to play an important role in the development and progression of certain aggressive types of breast cancer (15-30% of breast cancers)  Strongly associated with increased disease recurrence and a poor prognosis  Of 29 micro-dissected breast cancers: high levels of COX-2 protein in 14 our of 15 (93%) HER-2/neu-positive samples high levels of COX-2 protein in 4 our of 14 (29%) HER-2/neu-negative tumours Subbaramaiah et al., 1999
    18. 18. COX-2 expression and breast cancer prognosis  Cancer group: 57 primary breast cancer patients Control group: 27 patients consisting of fibro-adenoma and benign breast disease  Control group COX-2 was over-expressed in 0% Cancer group COX-2 was over-expressed in 74% breast carcinoma patients  COX-2 expression is directly correlated with ER negative (88.1%, p = 0.001) and also associated with higher NPI value (78.6%, p = 0.006).  COX-2 over-expression was found to correlate with aggressive phenotypic features, such as high histological grade, large tumour size, higher NPI value, ER negativity and HER-2/neu positivity Jana et al., 2012
    19. 19. COX-2, aromatase and oestrogen  About 75% of breast cancers are ER positive  Oestrogens are produced from androgens by the action of the enzyme aromatase  In postmenopausal women, plasma oestrogens result from peripheral aromatisation, particularly in adipose tissue  Many breast cancers, also contain aromatase with certain breast cancers able to synthesise oestrogens by intratumoural aromatase activity  COX-2 expression has been found to correlate with aromatase expression within human breast cancer tissue  Inflammation is a major activator of aromatase activity Brueggemeier et al., 2006
    20. 20. Arachidonic acid COX-1 COX-2 Constitutive ‘gate-keeping functions’ Induced Homeostatic function Gastrointestinal tract Renal tract Platelet function Macrophage differentiation Inflammation Cancer Block
    21. 21. Women’s Health Initiative (WHI) Observational Study designed to address some of the major causes of morbidity and mortality in an ethnically and geographically diverse sample of postmenopausal women Examined the effects of regular use of aspirin, ibuprofen and other nonsteroidal anti-inflammatory drugs (NSAIDs) on breast cancer risk  21% decrease in the risk of breast cancer among women who took NSAIDs at least twice a week for at least 5 years  28% decrease in the risk for women who used them for at least 10 years  statistically significant inverse linear trend of breast cancer incidence with the duration of NSAID use (P < 0.01) Harris et al., 2003
    22. 22. Data from 91 epidemiological studies examined the dose response of relative risk and level of NSAID intake for ten human malignancies  Results showed a significant exponential decline in the risk with increasing intake of NSAIDs (primarily aspirin or ibuprofen) for 7-10 malignancies  Daily intake of NSAIDs, primarily aspirin, produced risk reductions of 63% for colon, 39% for breast, 36% for lung, and 39% for prostate cancer  Significant risk reductions were also observed for oesophageal (73%), stomach (62%), and ovarian cancer (47%)  NSAID effects became apparent after five or more years of use and were stronger with longer duration Harris et al., 2005
    23. 23. Use of COX-2 inhibitors and breast cancer risk Meta-analysis of 6 cohort studies (number of cases ranged from 14 to 2414) and 8 case-control studies (number of cases ranged from 252 to 5882) (Khuder & Mutqi 2001) • Regular use of NSAID associated with 18% reduced risk of breast cancer Meta-analysis of 38 studies (16 case-control studies, 18 cohort studies, 3 casecontrol studies nested in well-defined cohorts, and 1 clinical trial) that included 2,788,715 subjects (Takkouch et al., 2008) • Regular use of aspirin associated with 13% reduced risk of breast cancer • Regular use of ibuprofen associated with 21% reduced risk of breast cancer
    24. 24. Use of COX-2 inhibitors and breast cancer risk Meta-analysis of 26 studies with 528,705 participants (Zhao et al., 2009) • Regular use of aspirin associated with 17% reduced risk of breast cancer • Regular use of ibuprofen associated with 19% reduced risk of breast cancer Meta-analysis of 33 studies (19 cohort studies, 13 case-control studies, and 1 randomized controlled trial ) that included 1,916,448 subjects (Luo et al., 2012) • Regular use of aspirin associated with 14% reduced risk of breast cancer
    25. 25. COX-2 Aromatase Prostaglandin COX-2 inhibitor Angiogenesis Oestrogen Facilitation of tumour growth Oestrogen dependant growth
    26. 26. Selective vs non-selective NSAIDS  Non-selective NSAIDs block both COX-1 and COX-2 [aspirin, ibuprofen (Brufen, Nurofen), naproxen (Naprosyn), diclofenac (Voltarol), etodolac (Lodine), and meloxicam (Mobic)]  Duel acting NSAIDS (COX/5-lipoxygenase inhibitors) [tepoxalin (Zubrin), meloxicam (Metacam)]  Selective COX-2 inhibitors – ‘coxibs’ [celecoxib (Celebrex), etoricoxib (Arcoxia)]  Main side effects associated with NSAIDs  gastrointestinal and renal effects (Lanas & Ferrandez 2013)  increased risk of heart attack, stroke heart failure or other thrombotic events or cardiovascular complications (Fanelli et al., 2013)
    27. 27. Selective COX-2 inhibitor drugs still have side effects  Merck & Co withdraws Rofecoxib (Vioxx, Vioxxacute) in September 2004 because evidence of an increased risk of confirmed serious thrombotic events (including myocardial infarction and stroke) compared to placebo, following long-term use  Pfizer withdraws Valdecoxib (Bextra) from the EU market in April 2005 because serious and potentially fatal skin reaction associated with its use outweighed the benefits  What are the non- pharmacutical alternatives?
    28. 28. Arachidonic acid EPA COX-1 COX-2 Constitutive ‘gate-keeping functions’ Induced Homeostatic function Gastrointestinal tract Renal tract Platelet function Macrophage differentiation Inflammation Cancer EPA
    29. 29. The role of EPA as a competitive inhibitor High arachidonic acid levels COX-2 Pro-inflammatory ‘cancer driving’ prostaglandins Increased EPA lowers arachidonic acid levels COX-2 Anti-inflammatory ‘cancer-suppressing prostaglandins Increased EPA lowers arachidonic acid levels EPA competes with AA for COX-2 Anti-inflammatory ‘cancer-suppressing prostaglandins
    30. 30. Intake of fish and marine n-3 polyunsaturated fatty acids and risk of breast cancer: meta-analysis of data from 21 independent prospective cohort studies  Twenty six publications, including 20,905 cases of breast cancer and 883,585 participants from 21 independent prospective cohort studies were eligible • 11 articles (13,323 breast cancer events and 687,770 participants) investigated fish intake • 17 articles investigated marine n-3 PUFA (16,178 breast cancer events and 527,392 participants) • 12 articles investigated ALA (14,284 breast cancer events and 405,592 participants) Zheng et al., 2013
    31. 31. Intake of fish and marine n-3 polyunsaturated fatty acids and risk of breast cancer: meta-analysis of data from 21 independent prospective cohort studies  Main findings: • No significant association was observed for fish intake or for short-chain omega-3 ALA intake • Marine omega-3 PUFA was associated with 14% reduction of risk of breast cancer (relative risk for highest v lowest category 0.86 (95% confidence interval 0.78 to 0.94), I(2)=54) • Dose-response analysis indicated that risk of breast cancer is reduced by 5% per 0.1g/day increment of dietary marine n-3 PUFA intake Zheng et al., 2013
    32. 32. Fish consumption patterns • • • • • Type (oily vs white; farmed vs wild) Omega-3 content/omega-6 content EPA to DHA ratio Cooking method Frequency of consumption Welch et al., 2002 Cod Tuna Salmon Haddock Plaice Herring Mackerel 29.9% 16.4% 14.2% 13.0% 7.6% 6.0% 3.0%
    33. 33. Dietary polyunsaturated fatty acids and breast cancer risk in Chinese women: a prospective cohort study (Shanghai Women’s Health Study) (Murff et al., 2011)  72,571 cancer free woman at recruitment (1996 to 2000) with 712 cancer cases reported at follow-up (2007)  Women who consumed the highest levels of omega-6 with the lowest amounts of marine derived omega-3 had 2-fold increased risk for breast cancer compared to women consuming the lowest amounts of omega-6 and highest amount of omega-3 PUFA intake  There was a statistically significant interaction between total omega-6 intake, marine-derived omega-3 intake and breast cancer risk
    34. 34. Specialty supplements and breast cancer risk in the VITamins And Lifestyle (VITAL) Cohort  Postmenopausal women (n = 35,016) recruited 2000-2002  Incident invasive breast cancers (n = 880) from 2000 to 2007  Data on supplement use (current versus past), frequency (days/week), and duration (years)  Current use of fish oil was associated with a 32% reduced risk of breast cancer with a ten-year average use suggestive of reduced risk (P trend = 0.09) Brasky et al., 2010
    35. 35. • Dietary intake of specific fatty acids and breast cancer risk among postmenopausal women in the VITAL cohort  Association between fatty acid intake and breast cancer risk (diet and supplements)  Total SFA was suggestive of an increased risk (HR = 1.47, 95% CI: 1.00-2.15, P = 0.09)  Total PUFA intake was not associated with increased risk of breast cancer risk (HR = 0.84, 95% CI: 0.65-1.09, P = 0.27)  Intake of eicosapentaenoic (HR = 0.70, 95% CI: 0.54-0.90, P = 0.04) and docosahexaenoic acid (HR = 0.67, 95% CI: 0.52-0.87, P = 0.01) were inversely associated with risk Sczaniecka et al., 2012
    36. 36. Modulating eicosanoids  Products (eicosanoids) derived from AA and EPA play a central role in inflammation and tissue homeostasis, and are directly implicated in cancer  Chronic inflammation is one of the foremost risk factors for different types of malignancies, including breast cancer  Inflammation in the tumour microenvironment is now recognised as one of the hallmarks of cancer  Regulating eicosanoid production may serve as a method to reduce risk as well as serve as a therapeutic target for inhibiting tumour growth
    37. 37. Modulation of angiogenesis by AA and EPA The formation of new blood vessels (angiogenesis), a critical process that affects tumour growth and dissemination (Szymczak et al., 2008)  EPA inhibit and AA stimulates major pro-angiogenic processes in human endothelial cells:      angiopoietin-2 (Ang-2) vascular endothelial growth factor (VEGF) basic fibroblast growth factor (bFGF) insulin-like growth factor-1 matrix metalloproteases (MMPs) that degrade the extracellular matrix, and play an important role in the migration of endothelial cells during angiogenesis
    38. 38. BRCA (breast cancer susceptibility protein) genes  BRCA1 and BRCA2 are human genes that belong to a class of genes known as tumour suppressors  As human caretaker genes they produce a protein responsible for repairing DNA or destroying cells if DNA cannot be repaired  Mutations in BRCA1 and BRCA2 damaged DNA is not repaired properly and this increases risks for cancers
    39. 39. Omega fatty acids and BRCA genes  EPA in vitro has been shown to mediate gene expression in human cells  AA down-regulates BRCA1 and BRCA2 expression which increases proliferation and anchorage independent growth of tumour cells  EPA increases BRCA1 and BRCA2 expression which decreases proliferation and increases apoptosis of tumour cells Bernard-Gallon et al., 2002
    40. 40. Arachidonic acid and eicosapentaenoic acid metabolism contribute to cancer risk and progression through pro-and anti-inflammatory lipid metabolites that stimulate cell proliferation, angiogenesis, and migration Azrad et al., 2013
    41. 41. EPA and cancer cachexia  Cachexia is a form of muscle wasting often associated with advanced stage cancer  Inflammatory cytokines appear to tilt the body's metabolism toward catabolism, the breakdown of muscle proteins and fat ultimately lead to a chronic state of wasting and malnourishment  Cachexia is a complication responsible for around 20% of cancer deaths  EPA supplementation decreases weight loss, promotes weight gain and increases survival times in patients affected with cancer cachexia  (Kanat et al., 2013)  Not all intervention studies show improvements and EPA supplementation may be more effective if provided earlier rather than later, when muscle loss is accelerated (Murphy et al., 2011)
    42. 42. GLA and breast cancer  GLA is metabolised to DGLA to produce anti-inflammatory eicosanoids  Addition of GLA to EPA reduces accumulation of AA (Barham et al., 2000)  GLA has a number of anti-tumour properties:  GLA reduces the secretion of SPARC and Ang-1 and inhibits the growth and metastasis of a variety of tumour cells (Cai et al., 1999; Watkins et al., 2005)  GLA significant reduces tumour ER expression and enhances tamoxifen efficacy in human breast cancer cells (Kenny et al., 2000)
    43. 43. EPA and breast cancer  EPA displaces AA and reduces the production of inflammatory products  EPA blocks the activity of cyclooxygenase-2 (COX-2) and the production of prostaglandin E2 (PGE2) inhibiting tumourigenesis  EPA reduces the production of pro-inflammatory cytokines TNF- , IL- 1  EPA increases BRCA1 and BRCA2 expression, inhibits proliferation and induces apoptosis (programmed cell death)  EPA down-regulates aromatase activity and decreases oestrogen production  EPA inhibits major pro-angiogenic processes  EPA may have potential in the treatment of cancer cachexia  Combining EPA with GLA offers synergistic benefits
    44. 44. AA and breast cancer   AA gives rise to key pro-inflammatory mediators involved in orchestrating cross-talk between tumour epithelial cells and immune cells AA drives inflammation within the tumour environment  Cyclooxygenase-2 (COX-2) is an enzyme over-expressed in many human cancers and converts AA to prostaglandin E2 (PGE2), which drives tumourigenesis  AA down-regulates BRCA1 and BRCA2 and promotes the proliferation, migration and invasiveness of cancer cells  AA stimulates aromatase activity and increases oestrogen production  AA stimulates major pro-angiogenic processes
    45. 45. Shifting the balance  AA and EPA content of cell membranes can be altered through consumption of omega-3 EPA (marine products/marine oils)  Changing the fatty acid composition of cell membranes affects • changes in membrane structure • products involved in immune function and the inflammatory cascade • cell signalling • gene expression and cell cycle control
    46. 46. ninab@igennus.com www.igennus.com drninabailey.co.uk 01223 421434
    47. 47. RBC content of EPA (%) The effect of EPA supplementation on red blood cell (RBC) membranes EPA content Maki & Rains, 2012 Time (weeks)
    48. 48. Fatty acid levels ( g/g) Changes in erythrocyte membrane omega-3 fatty acid levels following 12 weeks treatment with 1g ethyl-EPA Base line Boston et al., 2004 Week 12
    49. 49. References • • • • • • • • • • • Alfano, C. M., I. Imayama, et al. (2012). "Fatigue, inflammation, and omega-3 and omega-6 fatty acid intake among breast cancer survivors." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 30(12): 1280-1287. Azrad, M., C. Turgeon, et al. (2013). "Current Evidence Linking Polyunsaturated Fatty Acids with Cancer Risk and Progression." Frontiers in oncology 3: 224. Barham, J. B., M. B. Edens, et al. (2000). "Addition of eicosapentaenoic acid to gamma-linolenic acid-supplemented diets prevents serum arachidonic acid accumulation in humans." The Journal of nutrition 130(8): 1925-1931. Bernard-Gallon, D. J., C. Vissac-Sabatier, et al. (2002). "Differential effects of n-3 and n-6 polyunsaturated fatty acids on BRCA1 and BRCA2 gene expression in breast cell lines." The British journal of nutrition 87(4): 281-289. Bosma-den Boer, M. M., M. L. van Wetten, et al. (2012). "Chronic inflammatory diseases are stimulated by current lifestyle: how diet, stress levels and medication prevent our body from recovering." Nutrition & metabolism 9(1): 32. Boston, P. F., A. Bennett, et al. (2004). "Ethyl-EPA in Alzheimer's disease--a pilot study." Prostaglandins, leukotrienes, and essential fatty acids 71(5): 341-346. Brasky, T. M., C. M. Velicer, et al. (2010). "Nonsteroidal anti-inflammatory drugs and prostate cancer risk in the VITamins And Lifestyle (VITAL) cohort." Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 19(12): 3185-3188. Cai, J., W. G. Jiang, et al. (1999). "Inhibition of angiogenic factor- and tumour-induced angiogenesis by gamma linolenic acid." Prostaglandins, leukotrienes, and essential fatty acids 60(1): 21-29. Cathcart, M. C., J. Lysaght, et al. (2011). "Eicosanoid signalling pathways in the development and progression of colorectal cancer: novel approaches for prevention/intervention." Cancer metastasis reviews 30(3-4): 363-385. Fanelli, A., P. Romualdi, et al. (2013). "Non-selective non-steroidal anti-inflammatory drugs (NSAIDs) and cardiovascular risk." Acta bio-medica : Atenei Parmensis 84(1): 5-11. Harris, R. E., J. Beebe-Donk, et al. (2005). "Aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs in cancer prevention: a critical review of non-selective COX-2 blockade (review)." Oncology reports 13(4): 559-583.
    50. 50. References • • • • • • • • • • • Harris, R. E., R. T. Chlebowski, et al. (2003). "Breast cancer and nonsteroidal anti-inflammatory drugs: prospective results from the Women's Health Initiative." Cancer research 63(18): 6096-6101. Hawcroft, G., M. Volpato, et al. (2012). "The omega-3 polyunsaturated fatty acid eicosapentaenoic acid inhibits mouse MC-26 colorectal cancer cell liver metastasis via inhibition of PGE2-dependent cell motility." British journal of pharmacology 166(5): 17241737. Jana, D., D. K. Sarkar, et al. (2012). "Can cyclo-oxygenase-2 be a useful prognostic and risk stratification marker in breast cancer?" Journal of the Indian Medical Association 110(7): 429-433. Kanat, O., E. Cubukcu, et al. (2013). "Comparison of three different treatment modalities in the management of cancer cachexia." Tumori 99(2): 229-233. Kenny, F. S., S. E. Pinder, et al. (2000). "Gamma linolenic acid with tamoxifen as primary therapy in breast cancer." International journal of cancer. Journal international du cancer 85(5): 643-648. Lanas, A. and A. Ferrandez (2006). "NSAID-induced gastrointestinal damage: current clinical management and recommendations for prevention." Chinese journal of digestive diseases 7(3): 127-133. Luo, T., H. M. Yan, et al. (2012). "Aspirin use and breast cancer risk: a meta-analysis." Breast cancer research and treatment 131(2): 581-587. Maki, K. C. and T. M. Rains (2012). "Stearidonic acid raises red blood cell membrane eicosapentaenoic acid." The Journal of nutrition 142(3): 626S-629S. Murff, H. J., X. O. Shu, et al. (2011). "Dietary polyunsaturated fatty acids and breast cancer risk in Chinese women: a prospective cohort study." International journal of cancer. Journal international du cancer 128(6): 1434-1441. Murphy, R. A., E. Yeung, et al. (2011). "Influence of eicosapentaenoic acid supplementation on lean body mass in cancer cachexia." British journal of cancer 105(10): 1469-1473. Pender-Cudlip, M. C., K. J. Krag, et al. (2013). "Delta-6-desaturase activity and arachidonic acid synthesis are increased in human breast cancer tissue." Cancer science 104(6): 760-764.
    51. 51. References • • • • • • • • • • • • Rose, D. P. (1997). "Dietary Fat, Fatty Acids and Breast Cancer." Breast cancer 4(1): 7-16. Sczaniecka, A. K., T. M. Brasky, et al. (2012). "Dietary Intake of Specific Fatty Acids and Breast Cancer Risk Among Postmenopausal Women in the VITAL Cohort." Nutrition and cancer 64(8): 1131-1142. Singh-Ranger, G. and K. Mokbel (2002). "The role of cyclooxygenase-2 (COX-2) in breast cancer, and implications of COX-2 inhibition." European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 28(7): 729-737. Singh, B. and A. Lucci (2002). "Role of cyclooxygenase-2 in breast cancer." The Journal of surgical research 108(1): 173-179. Subbaramaiah, K., P. Michaluart, et al. (1999). "Resveratrol inhibits cyclooxygenase-2 transcription in human mammary epithelial cells." Annals of the New York Academy of Sciences 889: 214-223. Szymczak, M., M. Murray, et al. (2008). "Modulation of angiogenesis by omega-3 polyunsaturated fatty acids is mediated by cyclooxygenases." Blood 111(7): 3514-3521. Takkouche, B., C. Regueira-Mendez, et al. (2008). "Breast cancer and use of nonsteroidal anti-inflammatory drugs: a meta-analysis." Journal of the National Cancer Institute 100(20): 1439-1447. Vendramini-Costa, D. B. and J. E. Carvalho (2012). "Molecular link mechanisms between inflammation and cancer." Current pharmaceutical design 18(26): 3831-3852. Vona-Davis, L. and D. P. Rose (2013). "The Obesity-Inflammation-Eicosanoid Axis in Breast Cancer." Journal of mammary gland biology and neoplasia. Watkins, G., T. A. Martin, et al. (2005). "Gamma-Linolenic acid regulates the expression and secretion of SPARC in human cancer cells." Prostaglandins, leukotrienes, and essential fatty acids 72(4): 273-278. Welch, A. A., E. Lund, et al. (2002). "Variability of fish consumption within the 10 European countries participating in the European Investigation into Cancer and Nutrition (EPIC) study." Public health nutrition 5(6B): 1273-1285. Zhao, Y. S., S. Zhu, et al. (2009). "Association between NSAIDs use and breast cancer risk: a systematic review and meta-analysis." Breast cancer research and treatment 117(1): 141-150.
    52. 52. References • • Zheng, J. S., X. J. Hu, et al. (2013). "Intake of fish and marine n-3 polyunsaturated fatty acids and risk of breast cancer: meta-analysis of data from 21 independent prospective cohort studies." BMJ 346: f3706. Ziegler, R. G., R. N. Hoover, et al. (1993). "Migration patterns and breast cancer risk in Asian-American women." Journal of the National Cancer Institute 85(22): 1819-1827.

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