Role of progesterone receptor in bc
- 1. Role of Progesterone Receptor in Breast Cancer PRESENTED BY: Aleena Haqqi COURSE : CANCER GENETICS
- 2. Introduction To Breast Cancer Every 1 in 8 women It effects about 12% women worldwide Signs of breast cancer • A lump in the breast • A change in shape • Dimpling of the skin Cancer that develops from breast tissue
- 3. TYPES OF BREAST CANCER Cancers developing from the ducts are known as ductal carcinomas, while those developing from lobules are known as lobular carcinomas non-invasive breast cancer (carcinoma in situ) – found in the ducts of the breast (ductal carcinoma in situ, or DCIS) which has not spread into the breast tissue surrounding the ducts. invasive breast cancer – where the cancer cells have spread through the lining of the ducts into the surrounding breast tissue. This is the most common type of breast cancer. Lobule Duct cells Duct Lobular cells
- 4. Altered cellular pathways in BC A number of cellular pathways are altered in it including. These pathways are altered due to alteration in oncogenes; HER2, c-MYC, and RAS, the ER and PR genes, and the genes for cell cyclin D1 and E, and the tumor suppressor genes RB, TP53, and PTEN, and the breast cancer susceptibility genes BRCA1 and BRCA2. MAPK RB/E2F PI3K AKT mTOR TP53
- 5. Progesterone Introduction Members of the steroid hormone receptor family Act as ligand-activated transcription factors Function as direct activators of cytoplasmic signal transduction molecules. Including regulation of metabolism, cell-cycle progression, and survival Master regulator in female reproductive tissues It Controls developmental processes Proliferation Differentiation during the reproductive cycle and pregnancy. Role in BC PR also plays a role in progression of endocrine- dependent breast cancer the main action of PR is to regulate networks of target gene expression in response to binding its cognate steroid hormone, Progesterone
- 6. The isoforms PR-A and PR-B are the products of a single gene. the two principle PR isoforms PR-A (94 kDa) and PR-B (118 kDa). The isoforms contain a DNA binding domain and a ligand binding domain. N-terminal to the DBD is an AF-1 (activation function -1) and in the C-terminal direction a nuclear localisation signal and the LBD containing AF-2. It is believed that AF-1 is thought to mediate ligand-independent activity, whilst AF-2 is attributed wih ligand-dependent PR activation. The third isoform is the splice variant PR-C. PR-C can bind the ligand, but in the absence of the DBD would not be able to bind to PREs of target genes
- 7. Hormone Receptor Status in BC
- 9. Conventional Pathway Nuclear Receptor PR (Transcript Regulator) Ligand binding PR-A & PR-B Dimerization of PR Conformational Changes Translocation to Nucleus Binding to PRE
- 10. PG activation of progesterone receptor
- 12. Non-Classical Pathway Non-classical signaling has been shown to affect several processes including Oocyte development The growth of breast cancer cells, production of inflammatory cytokines Extracellular matrix (ECM) protein production induced by mechanical stimulation of myocytes
- 13. Routes of PGR signalling and the crosstalk with the ER signalling pathways
- 15. Progesterone Concenteration in BC Although both PRA and PRB are highly expressed in normal tissues, PRB protein concentrations reportedly are elevated in breast carcinoma. This results in a Decrease in the PRA:PRB ratio, which appears to be an important parameter for progesterone-mediated functions. The transcription of the PR gene is regulated by estrogen in breast and reproductive tissues.
- 16. Importance of PR in Hormone Therapy for BC Similar to ER‐α, PR status is a good predictor of tumor responsiveness to therapy. Nearly 50% of all ER+ tumors also are reported to be PR+ and approximately 75% of these ER/PR+ tumors respond positively to endocrine therapy. ER+, PR‐ tumors are reported to be less responsive to therapy, perhaps suggesting that PR may be necessary for positive therapeutic outcomes with hormone therapy. Alternatively, because ER is a key transcription factor for the activation of PR, lack of PR expression in these ER+/PR‐ cells also could suggest that the estrogen response pathway may not be functional in these tumors. Only a small fraction of tumors are ER‐/PR+ (< 5%) and they demonstrate an intermediate response to endocrine therapy.
- 17. Hormone Receptor-positive Or Hormone Receptor-negative Breast cancers can be classified based on receptor status or histology, HER2+ ER+/PR+ (about 70% of breast cancers) triple-negative breast cancer,(HR negative) Harmone receptor negative refers to the absence of these receptor proteins on tumor cells. Invasive lobular carcinomas.
- 18. Hormone Receptor HR+ Normal breast cells and some breast cancer cells have receptors that attach to the hormones estrogen and progesterone, and depend on these hormones to grow. These breast cancers can be treated with hormone therapy drugs. these cancers can sometimes come back many years after treatment. HR- have neither estrogen nor progesterone receptors. Treatment with hormone therapy drugs is not helpful for these cancers. These cancers tend to grow faster than hormone receptor-positive cancer
- 19. Estrogen Priming Estrogen is required for early breast development rather than progesterone/PR. Increased estrogen levels induce PR expression; this is known as ‘estrogen priming’ and PR-B plays role in latter stage of breast development. During pregnancy, progesterone signaling via PR in the epithelial compartment is required for branching and alveolar proliferation and differentiation.
- 20. Mutations in DNA repair genes such as BRCA1, BRCA2, CHEK2, PALB2, ATM, P53 and others are associated with elevated risk for breast cancers. Some gene mutations are linked to triple negative breast cancers (eg, BRCA1) others are linked to ER+ breast cancer (eg, CHEK2) while PR+ breast cancer is linked with BRCA2. BRCA1 mutation carriers have deregulated progesterone signaling leading to higher proliferation and DNA damage in a progesterone-sensitive RANK+ luminal progenitor subsets. Long-duration exposure to pharmacologic progestogen levels combined with estrogen, either through use of contraceptives or menopausal hormone therapy (primarily with estrogen+progestin formulations increases breast cancer risk.
- 21. Treatment Strategies for BC BRCA replacement gene therapy. reintroduction of BRCA genes into breast cancer cells have resulted in cell cycle arrest and apoptosis Another strategy involves BRCA1 overexpression in a breast cancer cell line, which confers resistance to chemotherapy. Utilization of BRCA1 antisense oligonucleotides restored drug sensitivity second generation platinum-based chemotherapeutic s.
- 22. Anti – RANKL Therapy The tumor necrosis factor (TNF) receptor RANK (TNFRSF11A) and its ligand RANKL (TNFSF11) regulate bone metabolism and control stem cell expansion and proliferationof mammary epithelial cells via the sex hormone progesterone RANKL and RANK have been implicated in the onset of hormone-induced breast cancer. RANK/RANKL are regulators for BRCA1 mutation-driven breast cancer. anti-RANKL therapy should be pursued as a preventative strategy for breast cancer.
- 23. Endocrine Therapy Endocrine Therapy If breast cancer is harmone receptor positive. Surgery
- 24. Endocrine therapy Endocrine therapy is the treatment of choice for patients with breast cancer expressing ER and/or PR The clinical usefulness of endocrine therapy has been proven in the Prevention, adjuvant and metastatic settings Postoperative adjuvant endocrine therapy provides approximately a 50% reduction in the development of recurrent disease metastatic breast cancer, which initially responds to endocrine therapy, always acquires endocrine resistance Which conclude half of breast cancers expressing hormone receptors (HR) are de novo resistant to endocrine therapy
- 25. Both de novo and acquired resistance to endocrine therapy are important problems in the management of breast cancer patients A number of classes of antiestrogen agents are approved for patients with early, advanced, or metastatic BC Selective Estrogen Receptor Modulators (Serms) Aromatase Inhibitors (Ais) A Selective Estrogen Receptor Degrader (SERD)
- 26. Mechanism of Resistance The estrogen receptor acts as a ligand dependent transcription factor and has two forms: Erα, encoded by ESR1 gene Erβ, encoded by ESR2 gene In 15–20% of cases, the resistance is associated with the activation of an ERα- independent proliferation mechanism It may be accompanied by a phenotypic change in cells, from ERα + to ERα−
- 27. Mechanism of Resistance As luminal B breast cancers are characterized by the lower expression of ERα than luminal A breast cancers there is a higher probability of ERα expression loss in luminal B breast cancers luminal B breast cancers are considered to have a higher risk of acquiring endocrine resistance than luminal A breast cancers
- 28. Mechanism of Resistance According to recent studies, several mechanisms are important in acquiring resistance to endocrine therapy, including; Molecular mechanisms of estrogen-independence ER switch The role of miRNA Autophagy Stemness (cancer stem like cells)
- 29. Ways to overcome Resistance The tumor cells have estrogen receptors and grow when exposed to this hormone Most of these cancers will respond to drugs that target the activity of the receptor E.g. selective estrogen receptor modulators (SERMs) work by competing with estrogen Selective estrogen receptor downregulators (SERDs) behave in a similar way, but they can also trigger the degradation of the receptors
- 30. Drugs that inhibit the production of estrogen have fewer side effects and are usually the first choice when treating patients with post-menopausal breast cancer The mutations in estrogen receptors can reduce the effectiveness of these drugs A hybrid SERM/SERD drug can overcome the resistance conferred by mutant receptors Hybrid SERM/SERD molecules, such as the drug bazedoxifene, display exceptional inhibitory activities in tumor models, but they degrade estrogen receptors very inefficiently Intense efforts are underway to identify new drugs that target estrogen receptors and also safe and tolerable
- 31. References http://atlasgeneticsoncology.org/Genes/GC_PGR.html Garg, D., Ng, S. S. M., Baig, K. M., Driggers, P., & Segars, J. (2017). Progesterone-mediated non- classical signaling. Trends in Endocrinology & Metabolism, 28(9), 656-668. Henry NL, Shah PD, Haider I, Freer PE, Jagsi R, Sabel MS. Chapter 88: Cancer of the Breast. In: Niederhuber JE, Armitage JO, Doroshow JH, Kastan MB, Tepper JE, eds. Abeloff’s Clinical Oncology. 6th ed. Philadelphia, Pa: Elsevier; 2020. Brufsky, A. M., & Dickler, M. N. (2018). Estrogen Receptor‐Positive Breast Cancer: Exploiting Signaling Pathways Implicated in Endocrine Resistance. The oncologist, theoncologist-2017 Szostakowska, M., Trębińska-Stryjewska, A., Grzybowska, E. A., & Fabisiewicz, A. (2019). Resistance to endocrine therapy in breast cancer: Molecular mechanisms and future goals. Breast cancer research and treatment, 173(3), 489-497
Editor's Notes
- #9: Classical and Non-Classical Pathways. Comparison of gene activation mediated by nuclear progesterone receptors is compared to ‘non-classical' progesterone-mediated cellular events. Non-classical signaling is complex, but can be considered to involve five overlapping but distinct mechanisms.
- #10: . It can activate the extra nuclear receptors, mPRs and PGRMC1 to influence cell proliferation and invasion via non-canonically routes. Both genomic and non-genomic modes of signaling may determine the relevance and the validity of PR in the progression, prognosis and management of breast cancer. The PR engages several systems, among them are PI3K/Akt/ MAPK and Wnt to influence cell adhesion, proliferation and apoptosis. The ER/PR axis is crucial in breast cancer, where the physiological outcome would be affected by the differential signaling initiated by the canonical and the non-canonical receptors. The crosstalk between the ER/PR axis and the growth factor/PI3K/Akt/mTOR system is also highly relevant. PGR mutations and polymorphism are infrequent in cancers. The polymorphic PROGINS has been linked, not indisputably, with cancer risk. Many SNPs have been identified, mostly inconsequential ones. Some may be related to breast, endometrial and colorectal cancer risk. PR produces good clinical outcome in breast cancer independently of ER. It displays greater correlation than ER with disease progression and prognosis. It may be differentially expressed in benign prostatic hyperplasia and progressive cancer. The expression may reflect androgen-insensitivity. PROGINS is said to increase ovarian cancer risk, but, paradoxically, reduce breast cancer risk. The use of progesterone antagonists or agonists has been advocated. PRs can act as activators or repressors of transcription, necessitating the identification of the functional PR/ER isoforms. Some new progestins, employed in HRT, have been claimed to prevent certain forms of cancer.
- #11: Fig. PG activation of progesterone receptor. Binding of PG to the inactive receptor complex induces a conformation change which leads to immunophilin and hsp dissociation, receptor dimerization, DNA binding, and recruitment of coactivators to facilitate communication with the basal transcription apparatus. PRE, progesterone response element.
- #12: Progesterone-Mediated Non-Classical Signaling pathways, Non-classical signaling has been shown to affect several processes including oocyte development, the growth of breast cancer cells, production of inflammatory cytokines, and extracellular matrix (ECM) protein production induced by mechanical stimulation of myocytes. P indicates phosphorylation; the question mark indicates that the mechanism is currently unknown. It can activate the extra nuclear receptors, mPRs and PGRMC1 to influence cell proliferation and invasion via non-canonically routes. Both genomic and non-genomic modes of signaling may determine the relevance and the validity of PR in the progression, prognosis and management of breast cancer. The PR engages several systems, among them are PI3K/Akt/ MAPK and Wnt to influence cell adhesion, proliferation and apoptosis. The ER/PR axis is crucial in breast cancer, where the physiological outcome would be affected by the differential signaling initiated by the canonical and the non-canonical receptors. The crosstalk between the ER/PR axis and the growth factor/PI3K/Akt/mTOR system is also highly relevant. PGR mutations and polymorphism are infrequent in cancers. PR produces good clinical outcome in breast cancer independently of ER. It displays greater correlation than ER with disease progression and prognosis. It may be differentially expressed in benign prostatic hyperplasia and progressive cancer. The expression may reflect androgen-insensitivity. PROGINS is said to increase ovarian cancer risk, but, paradoxically, reduce breast cancer risk. The use of progesterone antagonists or agonists has been advocated. PRs can act as activators or repressors of transcription, necessitating the identification of the functional PR/ER isoforms. Some new progestins, employed in HRT, have been claimed to prevent certain forms of cancer. Abbreviations: EGF, epidermal growth factor; EGFR, EGF receptor; ER, estrogen receptor; ERK, extracellular signal-regulated kinase; p38, p38 mitogen activated protein kinase; PKA, protein kinase A; PKC, protein kinase C; PKG, protein kinase G; PR, progesterone receptor.
- #14: Fig. the routes of PGR signalling and the crosstalk with the ER signalling pathways and Transactivation of EGFR, wnt/?-catenin ( CTNNB1) possibly influencing cell proliferation. mPR route to cell proliferation via PKA/camp activating the transcription factors CREB / CREM / ATF-1. Mpr working through the MAPK/akt and NO route to cell proliferation and invasion. The activation of the mapk/ erk1 ( mapk3)/erk2 ( mapk1) route leads to cell survival and proliferation. The ask1 ( map3k5)/jnk/p38 (signalling is a pro-apoptosis route There is considerable evidence of crosstalk between the ER/PR axis and the growth factor/PI3K/Akt/mTOR system as shown here. This can effectively explain the downregulation of PR. One has to be mindful also of the possibility that PR may be expressed as splice variants that may not be detected by the antibodies that are currently employed for PR assessment. The PR signalling system may engage in crosstalk with neighbouring genes. ER/PR may be co-ordinately regulated in breast cancer. However, it would be necessary to know whether the changes expression of ER and PR occur of their isoforms uniformly or in a differential fashion before any firm conclusions can be drawn concerning how this co-ordination takes place and what the outcome might be.
- #15: the effects of the canonical and non-canonical oestrogen receptor signalling. The isoforms can act as activators or repressors of transcription. PR-A is a ligand dependent repressor of PR-B. The PR-A and PR-B isoforms regulate different sets of target genes. The PR-B isoform is associated with increase in cell migration but not on cell proliferation or survival. PR-B activates many progesterone response genes by activating Src/MAPK signalling pathways, which can promote or inhibit cell proliferation (see also legend below). Progesterone induces endometrial proliferation and angiogenesis via the VEGF route. Both mPR and PGRMC1 can directly interact with progesterone and function independently of PR. PGRMC1 is also able to induce physiological effects by interaction with EGFR. Some of these pathways are not shown here. PGRMC1 : Progesterone receptor membrane component 1.