10. tumori ormono dipendenti
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10. tumori ormono dipendenti
- 1. Ormoni e carcinogenesi Prof.ssa Elisa Petrangeli
- 3. 1713 Ramazzini riscontrò alta incidenza di tumori mammari tra le suore a Padova 1842 Rigoni-Stern trovò che le suore avevano un rischio 3 volte maggiore di sviluppare tumore al seno rispetto alle altre donne 1889 Schinzinger stabilì che la malattia procedeva più lentamente in donne in post- menopausa 1896 Beatson riportò su Lancet la regressione di tumori mammari in stadio avanzato dopo castrazione chirurgica. Evidenze • studi epidemiologici: tempo di esposizione ad E tumori mammella ed endometrio • esperimenti in vitro: E-dipendenza della crescita cellulare
- 4. Ormoni che contribuiscono allo sviluppo di tumori endocrino- dipendenti. • Cancro della mammella estrogeni progestinici • Cancro dell’endometrio estrogeni progestinici • Cancro della prostata androgeni estrogeni
- 5. Rischio relativo di cancro della mammella.
- 6. What Are Estrogens? O Estrone Estradiol Steroid ring system OH HO HO
- 8. Ruolo fisiologico di ER ed estrogeni
- 9. Funzione degliFunzione degli estrogeniestrogeni Mantenimento e Proliferazione dell’epitelio mammario, endometriale, prostatico. I recettori per gli estrogeni sono ubiquitari Virtualmente presenti in tutti i tessuti e cellule Attenzione!Attenzione!
- 10. Superfamiglia dei recettori steroidei Potenti regolatori dello sviluppo e del differenziamento
- 12. Recettori estrogenici. • Esistono due isoforme distinte di recettore estrogenico (RE), alfa e beta. • Le due isoforme agiscono come omo- ed etero-dimeri e regolano in maniera differente la trascrizione di geni target: ● legandosi al promotore dei geni responsivi, o ● interagendo con altri fattori di trascrizione, come AP-1, Sp-1, NF-kB. • In generale, l’isoforma alfa stimola e l’isoforma beta inibisce la trascrizione di geni coinvolti nella rispota proliferativa
- 13. Isoforme del recettore estrogenico L’espressione delle isoforme RE-α and RE-β è tessuto e cellulo-specifica. Tessuti responsivi agli estrogeni: • classici (alti livelli di RE-α): utero, mammella, placenta, osso, sistema cardiovascolare, alcune aree del CNS • non classici: (alti livelli di RE-β): testicoli, polmone, epitelio intestinale, muscolo, tiroide, pelle, tratto urinario, etc.
- 14. La risposta biologica varia a seconda dei livelli di recettori ormonali espressi sulle cellule bersaglio.
- 15. Copyright ©2005 The Endocrine Society Bjornstrom, L. et al. Mol Endocrinol 2005;19:833-842 . Schematic Illustration of ER Signaling Mechanisms
- 16. SIGNALLING DEL RETTORE ESTROGENICO NISS MISS Membrane-Initiated Steroid SignalingNuclear -initiated Steroid Signaling
- 17. La risposta è cellulo- e tessuto- specifica, condizionata dai: livelli di espressione delle isoforme recettoriali (dimeri/eterodimeri), dal promotore in esame, dalla presenza di corepressori e coattivatori Meccanismo di attivazione e di azione trascrizionale dei Recettori Estrogenici, attivati dal ligando
- 19. Meccanismo d’azione dei recettori nucleari Transattivazione o repressione di geni target
- 22. I geni bersaglio direttamente sotto il controllo degli ER sono coinvolti in proliferazione e differenziamento A. Recettori progestinici B. TGF-α, IGF-1, EGF, ERB2, EGF-R C. Catepsina D, HSp27, cMyc, cfos, cJun, RaRα D. Ciclina D, B1, D1 ed E, pS2 E. HDAC
- 23. 3 ligando-indipendente Cross-talk con altre vie di segnale mitogenetiche EGF IGF-1 Azione diretta su ER Modulando attività “coregulation” di ER P -P160 Reclutamento co-attivatori ↑Trascrizione geni bersaglio Attività trascrizionale x interazione con CBP/P300 ↑ Attività HAT di CBP ERα/AF-1 MAP-K MAP-K P
- 24. 4 non genomica Segnali precoci nelle cellule bersaglio ERs associati alla membrana citoplasmatica Segnali diversi da quelli determinati dall’azione nucleare ER- nucleo E
- 26. Action of estrogens on the pro- inflammatory cytokines activity Activated ER directly inhibits IL-6 and TNF-α expression via NF-kB- and AP-1-dependent mechanisms. Estrogens also modulate the expression of inducible pro- inflammatory genes (i.e.: iNOS and COX-2); Membrane ERs is involved in other cytokine regulation. COX-2
- 27. Role of estrogens in the immune response IL-12 IL-18
- 28. Role of the endocrine system in regulating the formation of Th1 or Th2 cells • The balance of DHA to cortisol regulate the progression of Th cells to Th1 or Th2 phenotype. • Aging is associated to a decrease in plasma DHA concentration, favoring a Th2 cytokine response with increased secretion of Il-6, which can stimulate tissue aromatase. (Endocrine Review, 1997, 18: 701-715)
- 29. Estrogeni: Proliferazione o antiproliferazione? Dipende da: -Ligando -Isoforme recettoriali alfa e beta -Cellula o tessuto bersaglio -Complesso di trascrizione genica -Cofattori e segnali costimolatori o antagonisti -Disponibilità dei geni da attivare
- 30. Progressiva diminuzione dell’espressione dell’isoforma beta del recettore estrogenico nella progressione di: •Ca. della mammella •Ca. ovarico •Ca. prostatico •Ca. colon
- 31. Ipotetico meccanismo d’azione del REβ sulla risposta proliferativa cellulare
- 32. Rappresentazione schematica dello sbilanciamento del rapporto REα/REβ nella progressione tumorale
- 33. SERM o Selectiveo Selective Estrogen ReceptorEstrogen Receptor ModulatorsModulators Si legano alle isoforme dei recettori estrogenici con affinità ed azione trascrizionale diverse, determinando una espressione genica (estrogeno-agonista od -antagonista) che appare cellulo- e tessuto-specifica Ligandi naturali: (fitoestrogeni, cumestrolo, etc) e sintetici (tamoxifene, raloxifene, etc)
- 34. Isoforme del recettore estrogenico e SERMs naturali Azione tessuto-specifica dei RE: dipende dai livelli di espressione dei RE e dai livelli di altri cofattori. I modulatori selettivi degli estrogeni (SERMs) sono ligandi del RE che possono avere effetti diversi o opposti a seconda della isoforme di RE cui si legano ed agiscono come agonisti o come antagonisti in tessuti diversi. Alcuni componenti dei cibi, come la genisteina e daidzeina agiscono come SERMs naturali, legandosi con maggior affinità al RE-β. .
- 36. Affinità relative di differenti ligandiAffinità relative di differenti ligandi alle isoformealle isoforme αα ee ββ del recettore estrogenicodel recettore estrogenico LigandoLigando IsoformaIsoforma αα IsoformaIsoforma ββ 17-β-estradiolo 100 100 17-α-estradiolo 58 11 Estriolo 14 21 Estrone 60 37 4-idrossiestradiolo 13 7 2-idrossiestrone 2 0.2 Tamoxifen 4 3 Raloxifene 69 16 Genisteina 4 87 Cumestrolo 20 140 Daidzeina 0.1 0.5
- 37. There is growing interest in the possible health threat posed by endocrine-disrupting chemicals (EDCs), which are substances in our environment, food, and consumer products that interfere with hormone biosynthesis, metabolism, or action resulting in a deviation from normal homeostatic control or reproduction
- 38. Endocrine-Disrupting Chemicals.1 EDCs at certain concentrations can cause disruption to endocrine systems. They include: • pesticides (e.g. DDT, vinclozolin, TBT, atrazine), • persistent organochlorines and organohalogens (e.g. PCBs, dioxins, furans, brominated fire retardants), • alkyl phenols (e.g. nonylphenol and octylphenol), • heavy metals (e.g. cadmium, lead, mercury), • phytoestrogens (e.g. isoflavoids, lignans, -sitosterol),β • synthetic and natural hormones (e.g. -estradiol,β ethynylestradiol), • epigenetic DNA methylation.
- 39. Endocrine-Disrupting Chemicals.2 EDCs can cause endocrine disruption through a range of mechanisms by acting as: – (1) environmental estrogens or SERMs, e.g. methoxychlor, bisphenol A, dioxin, endosulfan; – (2) environmental antiandrogens, e.g. vinclozolin, DDE, – (3) toxicants that reduce steroid hormone levels, e.g. fenarimol, endosulfan; – (4) toxicants that affect reproduction primarily through effects on the central nervous system, e.g. dithiocarbamate; – (5) others (e.g. interacting with PPARs, altering thyroid hormone levels, aromatase activity). •
- 40. EDCs interact with hormone receptors EDCs were originally thought to exert actions primarily through: • nuclear hormone receptors, including estrogen receptors (ERs), androgen receptors (ARs), progesterone receptors, thyroid receptors (TRs), retinoid receptors, Peroxisome proliferator-activated receptor (PPAR) and • Nonnuclear steroid hormone receptors (e.g., membrane ERs), nonsteroid receptors (e.g., neurotransmitter receptors such as the serotonin receptor, dopamine receptor, norepinephrine receptor), orphan receptors [e.g., aryl hydrocarbon receptor (AhR)—an orphan receptor], enzymatic pathways
- 41. EDC Exposed animal and effects Possible translation to the clinical condition Potential mechanisms Vinclozoli n Fetal rat: multisystem disorders including tumors Epigenetic: altered DNA methylation in germ cell line; reduced ER expression in uterus DES Fetal mouse: transmitted susceptibility to malignancies Vaginal carcinoma in daughters of women treated with DES during pregnancy DDT/DDE Immature female rat: sexual precocity Precocious and early puberty Neuroendocrine effect through estrogen receptors, kainate receptors, and AhRs Reduced fertility in daughters of exposed women <15 yr: increased breast cancer risk BPA Inhibited mammary duct dev and increased branching Miscarriages Inhibition of apoptotic activity in breast; Increased mammary gland density, Increased number of progesterone receptor-positive epithelial cells; Endometrial stimulation Reduced sulfotransferase inactivation of estradiol; Early puberty 0>Nongenomic activation of ERK1/2 PCBs Fetal rat: neuroendocrine effects in two generations Actions on estrogen receptors, neurotransmitter receptors Dioxins Fetal rat: altered breast dev, increased mammary cancer Inhibition of cyclooxygenase2 via AhR Early pubertal rat: blocked ovulation
- 42. Effetti di spill-over degli endocrine disruptors NormaleNormale rispostarisposta deglidegli estrogeniestrogeni NormaleNormale rispostarisposta delladella diossinadiossina RispostaRisposta delladella diossinadiossina con spill-con spill- over delover del recettorerecettore estrogenicoestrogenico
- 44. Essential for normal growth & development of the breast Important factor in breast cancer • Decreases time for mutation repair Estrogen and other reproductive hormones cause proliferation of breast cells • Key event during the tumor promotion Proliferating cells at risk to undergo initiation, promotion and progression stages of cancer formation Proliferation – Cell Multiplication
- 45. Development of the Breast Ductal Tree Differentiation Occurs With Pregnancy 2 years After Puberty After Pregnancy Birth Lobules
- 46. Puberty Sexual Maturity Pregnancy Lactation Terminal End Bud Lobule Type 1 Lobule Type 2 Lobule Type 3 Lobule Type 4 60 22 4 1 Level of Proliferation Differentiation of A Breast Lobule Growth to a Functioning Entity
- 47. Breast Lobule Types Puberty Pregnancy Lactation Lobule Type2 Lobule Type3 Lobule Type4 Lobule Type1 Containscellsat tobecomebreast cancer highestrisk -cellsthatare -cellsthatare proliferating not differentiated Premenopausal WomenHave Different LobuleTypes 80%-100%type3lobules Childbearing 30%-35%type 2lobules 5%-10%type 3lobules Childless 50%-60%type1lobules
- 48. Key Biological Factors for Breast Cancer Risk 1) Number of Cells Risk to become breast tumors - Cells which are not differentiated - Cells which are proliferating 2) Estrogen and other hormones - Levels of these hormones in blood - Level of receptors for these hormones Cells Susceptible to Become Tumors - Measure of vulnerability to cancer
- 49. FATTORI DI RISCHIO Menarca precoce e menopausa tardiva Obesità post-menopausale Terapia sostitutiva con estrogeni Nulliparità Primiparità tardiva FATTORI PROTETTIVI Gravidanza precoce Lattazione prolungata Esercizio fisico TUMORE MAMMARIO
- 50. Importante capire i meccanismi attraverso i quali gli Estrogeni determinano un aumento della proliferazione cellulare nei tumori estrogeno-associati
- 53. Metaboliti dell’estradiolo potrebbero avere un’azione mutagenica attraverso una pathway che coinvolge l’enzima 1B1 citocromo P450. Questa catalisi converte E2 in catechol- estrogen4-hydroxyestradiol (4-OHE2), che è ulteriormente metabolizzato a 3,4-estradiol-quinone. Questo metabolita lega covalentemente le molecole di guanina o adenina del DNA, attivando l’enzima glicosidasi che attraverso un processo di depurinazione provoca punti di mutazione (Yager 2000; Cavalieri 2000) E2 legandosi al proprio recettore stimola geni coinvolti nella proliferazione cellulare, aumentando la velocità del ciclo cellulare a scapito dei processi di riparazione del DNA. L’aumentata mitosi può portare a propagazioni di mutazioni già presenti (Preston-Martin et al., 1993)
- 57. Estrogen-Induced Proliferation of Existing Mutant Cells Mutant breast cells (caused by error, inheritance, and/or environmental factors) Estrogen stimulation
- 58. Estrogen-Induced Proliferation and Spontaneous New Mutations Normal breast cell Increased proliferation Estrogen stimulation Mistake in DNA duplication
- 59. MODULAZIONE DELLA PRODUZIONE di CATEPSINA D. Catepsina D: proteasi lisosomiale regolata dall'estrogeno in grado di digerire la matrice extracellulare e la membrana basale, facilitando la migrazione e l'invasione di cellule cancerose. Marcatore Prognostico in diversi tipi di tumori, a causa delle attività mitogeniche e proteolitiche, INVASIONE TUMORALE
- 62. Antiestrogens Estrogen receptor Binding to DNA Estrogen receptor Coactivator binds Genes are activated Estrogen Coactivator cannot bind to antiestrogen- bound receptor No gene activation Antiestrogen Binding to DNA
- 66. Tamoxifen and Breast Cancer Treatment Breast cancer surgically removed Reduced risk of cancer recurrence Treatment with tamoxifen
- 67. Tamoxifen as a Cause of Uterine Cancer Decreased cancer risk TamoxifenEstrogen Uterine receptor activated Estrogen receptor in uterine endometrial cell Endometrial cell proliferation Breast receptor not activated Estrogen receptor in breast cell blocked No breast cell proliferation Increased cancer risk
- 68. Estrogen Receptor-Negative Breast Cancer Estrogen Estrogen receptor- negative breast cancer Estrogen receptor- positive breast cancer Cell proliferation • Not controlled by estrogen • Not inhibited by tamoxifen Cell proliferation • Controlled by estrogen • Inhibited by tamoxifen Estrogen receptor Tamoxifen inhibits
- 71. MECCANISMI MOLECOLARI DI RESISTENZA ALLA TERAPIA ORMONALE IN TUMORI ER-POSITIVI Mutazioni a carico di ER sensibilità al ligando reclutamento di co-attivatori 1) 2) Modificazioni post-traduzionali di ER e/o Aumentata attività di GF attivazione ligando-indipendente 3) espressione di co-attivatori o downregulation di co-repressori 4) Attivazione di vie di trasduzione di segnali che dipendono da effetti non-genomici di ER
Editor's Notes
- Estrogens are a family of related molecules that stimulate the development and maintenance of female characteristics and sexual reproduction. The natural estrogens produced by women are steroid molecules, which means that they are derived from a particular type of molecular skeleton containing four rings of carbon atoms, giving the shape shown here. The most prevalent forms of human estrogen are estradiol and estrone. Both are produced and secreted by the ovaries, although estrone is also made in the adrenal glands and other organs.
- Catepsina D: proteina lisosomiale estrogeno-indotta con attività enzimatica proteolitica marcata ruolo nell’invasione
- CONTRACCETTIVI ORALI: l’epitelio dei dotti mammari ha &gt; attività mitotica nella fase tardiva del ciclo mestruale per effetto di estrogeni e progesterone i contraccettivi orali stimolano l’epitelio duttale per un periodo di tempo più lungo di quello fisiologico favorendo la cancerogenesi………
- Cancer is caused by DNA damage (i.e., mutations) in genes that regulate cell growth and division. Some mutations are inherited, while others are caused by exposure to radiation or to mutation-inducing chemicals such as those found in cigarette smoke. Mutations also can occur spontaneously as a result of mistakes that are made when a cell duplicates its DNA molecules prior to cell division. When cells acquire mutations in specific genes that control proliferation, such as proto-oncogenes or tumor suppressor genes, these changes are copied with each new generation of cells. Later, more mutations in these altered cells can lead to uncontrolled proliferation and the onset of cancer. (For more information on how gene mutations cause cancer, see Understanding Cancer.)
- Enzimi a citocromo P450 catalizzano il metabolismo ossidativo degli estrogeni 3-4 addotti instabili con A e G che portano a depurinazione e mutazione IN BLU Vie di detossificazione a scopo protettivo attive nel breast: metilazione e coniugazione con il glutatione
- estrogen does stimulate cell proliferation. Therefore, if one or more breast cells already possesses a DNA mutation that increases the risk of developing cancer, these cells will proliferate (along with normal breast cells) in response to estrogen stimulation. The result will be an increase in the total number of mutant cells, any of which might thereafter acquire the additional mutations that lead to uncontrolled proliferation and the onset of cancer. In other words, estrogen-induced cell production leads to an increase in the total number of mutant cells that exist. These cells are at increased risk of becoming cancerous, so the chances that cancer may actually develop are increased.
- Even in women who do not have any mutant breast cells, estrogen-induced proliferation of normal breast cells may still increase the risk of developing cancer. The reason involves DNA. A cell must duplicate its DNA molecules prior to each cell division, thereby ensuring that the two new cells resulting from the process of cell division each receive one complete set of DNA molecules. But the process of DNA duplication occasionally makes mistakes, so the resulting DNA copies may contain a small number of errors (i.e., mutations). If one of these spontaneous mutations occurs in a gene that controls cell growth and division, it could lead to the development of cancer. Proliferation of normal cells from exposure to estrogen creates a vulnerability to spontaneous mutations, some of which might represent a first step on the pathway to cancer.
- Since estrogen can promote the development of cancer in the breast and uterus, it seems logical to postulate that substances that block the action of estrogen might be helpful in preventing or treating these two types of cancer. This rationale has led scientists to work on the development of “antiestrogen” drugs that can block the action of estrogens and thereby interfere with, or even prevent, the proliferation of breast and uterine cancer cells. Antiestrogens work by binding to estrogen receptors so that the estrogen molecules themselves cannot bind to those receptors. This also blocks estrogen from activating genes for specific growth-promoting proteins.
- In women who have breast cancer, proliferation of the breast cancer cells is often driven by estrogen, just as in the case of normal breast cells. Since tamoxifen can block the effects of estrogen on breast cells, scientists predicted that breast cancer could be treated by using tamoxifen to interfere with estrogen-induced cell proliferation. Based on encouraging results obtained in experimental trials, tamoxifen was first approved for such use in breast cancer treatment in the 1970s. The first step in treating women with breast cancer is to surgically remove the cancer from the breast. It is difficult to be certain that every cancer cell has been removed at the time of surgery because some breast cancer cells could have spread to surrounding tissues or other organs prior to the operation. Therefore, women often receive some type of treatment after surgery (adjuvant therapy) to prevent the growth of any cancer cells that might remain in the body. Studies show that when tamoxifen is used for this purpose, the risk of cancer recurrence is reduced.
- Although tamoxifen has been useful both in treating breast cancer patients and in decreasing the risk of getting breast cancer in women at high risk, it also has some serious side effects. These side effects arise from the fact that while tamoxifen acts as an antiestrogen that blocks the effects of estrogen on breast cells, it mimics the actions of estrogen in other tissues such as the uterus. Its estrogen-like effects on the uterus stimulate proliferation of the uterine endometrium and increase the risk of uterine cancer.
- Mechanism of action of aromatase inhibitors and tamoxifen. Oestradiol binds to the oestrogen receptor (ER), leading to dimerization, conformational change and binding to oestrogen response elements (EREs) upstream of oestrogen-responsive genes including those responsible for proliferation. Tamoxifen competes with oestradiol for ER binding whereas aromatase inhibitors reduce the synthesis of oestrogens from their androgenic precursors.