The Efficacy of Tamoxifen and Other Pharmaceuticals in Treating Breast Cancer Shawn Potteiger, Justin Perkins Biol 479 Breast Cancer Two primary causes: Hormone receptor-positive breast cancer Estrogen and progesterone stimulate cell growth Referred to as Estrogen Receptor-positive (ER+) HER2-positive cancer cells allow cancer cells to grow quickly Hormone receptor-negative breast cancer Caused by genetic characteristics Example: BRCA1 gene Estrogen A steroid hormone derived from cholesterol Primarily functions as a female sex hormone Develop secondary sexual characteristics Involved in the menstrual cycle Estrogen, continued Other functions of estrogen: Structural Increase bone formation Thicken the vaginal wall Increases HDL (high-density lipoprotein) and decreases LDL (low-density lipoprotein) Aid in coagulation of blood Support hormone-sensitive breast cancers Estrogen Receptor Different forms of Estrogen Receptors: Estrogen Receptor ? alpha (ER?) Nuclear receptor Estrogen Receptor ? beta (ER?) Nuclear receptor G Protein-coupled Estrogen Receptor (GPER) Integral membrane protein Member of the rhodopsin-like family of G Protein-Coupled Receptors (GPCRs) Receptor Distribution ER? Endometrium, breast cancer cells, ovarian stromal cells, and in the hypothalamus Stromal cells ? epidermal connective tissue cells of the ovary that release growth factors and promote cell division ER? Kidney, brain, bone, heart, lungs, intestinal mucosa, prostate, and endothelial cells GPER Hypothalamus, pituitary gland, adrenal medulla, kidney medulla, and developing follicles of the ovary ER+ Breast Cancer Estrogen receptors are over-expressed in about 70% of breast cancers Two theories of how excess estrogen receptor cause tumorigenesis Estrogen receptor binding causes mammary cell proliferation Increased cell division and DNA replication Increased chance of mutations Estrogen metabolism creates genotoxic waste ER+ Breast Cancer, continued ER? has been shown to be heavily involved in tumor formation Cell cycle, apoptosis, and DNA repair are all compromised and disrupted The result is uncontrolled growth and tumor formation Tamoxifen Discovered by Dora Richardson of ICI Pharmaceuticals (now AstraZeneca) in 1962 Also known as Tamoxifen citrate, or the brand names: Nolvadex Istubal Valodex Antagonist of the estrogen receptor in breast tissue An antagonist binds to the receptor but does not produce a response Blocks the action of estrogen (the agonist) http://doctor2008.files.wordpress.com/2009/12/tamoxifen1.jpg http://2.bp.blogspot.com/_CACb3jWARoU/SIqR0HNRtII/AAAAAAAAA8U/5ZbuKyusC-g/s320/tamoxifen.jpg Tamoxifen as an Antagonist Some cells require estrogen to grow Tamoxifen itself is not the active antagonist It is metabolized into compounds that bind to the estrogen receptor but do not activate it Blocking estrogen binding to the estrogen receptor blocks cell growth http://www.med.wayne.edu/physiology/facultyprofile/skafar/Figures%20and%20publications/figure3.jpg Tamoxifen Metabolites Perform the Action Tamoxifen is metabolized in the liver by a cytochrome P450 isoform Active metabolites are 4-hydroxytamoxifen and N-desmethyl-4-hydroxytamoxifen (endoxifen) Metabolites have 30-100 times more affinity for the estrogen receptor than Tamoxifen itself 4-hydroxytamoxifen Tamoxifen Endoxifen http://www.sigmaaldrich.com/united-states.html Tamoxifen Metabolites Perform the Action, continued http://sitemaker.umich.edu/rae/files/tam_metabolism.jpg Tamoxifen Metabolites Perform the Action, continued The estrogen receptor/metabolite complex recruits other proteins Co-repressors help to stop genes from being switched on by estrogen Tamoxifen must also block growth hormone HER2 HER2 = ?Human Epidermal growth factor Receptor 2? The estrogen receptor/metabolite complex suppresses expression of the pro-proliferative HER2 protein http://www.web-books.com/eLibrary/Books/B0/B18/OPS/images/image015.jpg Tamoxifen Mechanism of Action Tamoxifen binds estrogen receptors on tumors and other tissues Makes a nuclear complex that decreases DNA synthesis Cells do not move through the S (DNA synthesis) phase Cells remain in the G0 and G1 phases Works as a nonsteroidal, cytostatic agent Cytostatic means that it blocks/prevents cancerous cells from forming The opposite would be a cytocidal agent that kills cancerous cells http://www.le.ac.uk/ge/genie/vgec/images/cellcycle.png Tamoxifen Side Effects Prevents bone loss Helps prevent osteoporosis Linked to endometrial cancer in some women Risk of cancer can double or quadruple in prolonged treatment As a result, Tamoxifen is usually not given for more than 5 consecutive years Can reduce cognition and semantic memory scores Beneficial effects on serum lipid profiles in post-menopause women Can cause ?fatty liver? though Reduction in libido http://www.web-books.com/eLibrary/Books/B0/B18/OPS/images/image019.jpg Emerging Tamoxifen Research It is estimated that although effective, only about 66% of women actually benefit from tamoxifen treatment due to various reasons Treatment with tamoxifen usually involves a 5 year schedule following surgery or initial round of treatment Geneticists have discovered a gene, FKBPL, which predicts how women respond to this SERM Women that express high levels of this gene have a correlation with chances of survival and respond better to tamoxifen treatment Other Breast Cancer Drugs Tamoxifen ? SERM (Selective Estrogen-Receptor Modulator) Although Tamoxifen commonly used, there are other types of drugs for breast cancer as well: Aromatase Inhibitors Biologic Response Modifiers Other Hormonal Therapies Aromatase Inhibitors Very commonly prescribed as an alternative treatment to Tamoxifen and SERMs (generally after SERM treatment). Most commonly prescribed to postmenopausal women for treatment of breast and ovarian cancers. Aromatase Inhibitors, continued Two categories: - Steroidal inhibitors (exemestane) Considered ?permanent? ? forms irreversible bond with the aromatase enzyme complex. - Non-steroidal inhibitors (anastrozole) Inhibition through reversible competition Aromatase Inhibitors, continued What is aromatase? An enzyme Part of the cytochrome P450 family of enzymes Responsible for the synthesis of estrogens More technically, aromatase converts the leftmost ring into an aromatic state This is done through oxidation and removal of the methyl group attached in between the leftmost and adjacent carbon rings By disrupting this enzyme, estrogen production is decresed Aromatase Inhibitors, continued ATAC Trial (Arimidex, Tamoxifen Alone or in Combination) Massive study including almost 10,000 women Purpose was to study whether certain aromatase treatments were more effective in treating localized estrogen receptor positive (ER) breast cancers than Tamoxifen. Results showed that anastrazole receiving patients had significantly more survival events and survival rates Biologic Response Modifiers These drugs bind with certain proteins on breast cancer cells, inhibiting growth. Herceptin is the most common example. Herceptin Monoclonal antibody therapy Attaches to the HER2 (also written HER2/neu) receptor located on breast cancer cells. Approx. 30% of breast cancer patients overexpress HER2 receptors, which can allow for aggressive cancer growth. Tamoxifen treatment usually downregulates expression of this receptor type via estrogen receptor blocking. Other Hormonal Therapies Generally used to treat cancers which depend on estrogen for growth and survival Used concomitantly or independently of other therapeutics such as aromatase inhibitors and SERMs Other Hormonal Therapies, con. Faslodex: Fulvestrant; Used in women who have become resistant or non-responsive to tamoxifen treatments; instead of binding to estrogen receptors, it destroys them in cancer cells. Zoladex: Goserelin acetate; a synthetic form of LHRH. Blocks the release of estrogen in breast cancer patients through negative feedback inhibition (and testosterone in male prostate cancer patients). References Breast Cancer MedicineNet.com, 2010. Web. 24 Jan. 2010. . Estrogen Receptor/SERMs National Cancer Institute, 2006. Web. 24 Jan. 2010. .>. Tamoxifen Breastancer.org, 2010. Web. 24 Jan. 2010. . Vanden Heuvel, Jack. "Molecular and Cellular Toxicology." The Pennsylvania State University, University Park. 2010. Lecture. References (con.) Mokbel K (2002). "The evolving role of aromatase inhibitors in breast cancer". Int J Clin Oncol 7 (5): 279?83. Howell A, et al.; ATAC Trialists Group. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 2005 Jan 1-7;365(9453):60-2. Attar E, Bulun SE. Aromatase inhibitors: the next generation of therapeutics for endometriosis? Fertil Steril 2006;85:1307-18. References (con.) Imaginis.com, 2010. Web. 28 Jan 2010.
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