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Estrogen Receptors & SERMS; the Mechanism to Breast Cancer Rita Youanis Almost everyone knows or is related to someone that has been affected by breast cancer. I myself was personally affected when my aunt passed away from breast cancer several years ago. My interest in estrogen receptors in correlation with breast cancer was further sparked after reading What Your Doctor May Not tell You About Menopause written by Dr. Lee with Virginia Hopkins. She interestingly discusses Xenoestrogens, petrochemicals in the environment that are chemically to estrogen, mimicking its effects on the human body. I will be discussing how estrogen receptors are used to prevent breast cancer, particularly in reference to the drug, Tamoxifen. Tamoxifen is currently used to treat and prevent some types of breast cancer that require estrogen to grow. What are Estrogens? Estrogens are a group of hormone molecules that stimulate the development and maintenance of female characteristics and sexual reproduction. They function as the most prevalent forms of human estrogen are derived from steroid molecules which contain four rings of carbon atoms (see figure 1). There main targets tissues are the estrogen receptors in the breasts and the uterus. Theses receptors are usually found in the cells nucleus where they trigger gene activation. The binding of estrogen to its receptor causes conformational changes in the receptor. The estrogen and estrogen receptor complex can then bind to specific DNA sites, estrogen response elements, which are nearby genes controlled by estrogen. The estrogenreceptor complex then binds to coactivator proteins causing the nearby genes to become active. Those active genes produce molecules of messenger RNA, which make different types of proteins that affect the cells behavior. In target tissues like the breast and the uterus estrogen causes cellular proliferation. For example in breast tissue, estrogen causes the proliferation of cells lining the milk glands preparing the breast to produce milk. Estrogen also causes proliferation of cells forming the inner lining of the uterus, endometrium, preparing it for a possible embryo. During menstruation estrogen levels fall and the endometrium disintegrates.

Estrogen can be beneficial in preparing the breast and uterus for sexual reproduction. Unfortunately these estrogen induced cycles can cause cancer. Cancer is caused by DNA damage, mutations in genes that regulate cell growth and division. Some mutations can be inherited or caused by chemicals in the environment while others can occur spontaneously. Mutations occur spontaneously as a result of mistakes that occur when a cell duplicates its DNA molecules prior to cell division. Although estrogen doesn't directly cause DNA to be mutated it does cause cell proliferation. If a breast cell or uterus cell already possesses a DNA mutation that increases the risk of developing cancer, estrogen will cause a these cells to proliferate increasing the chances of cancer. If a breast cell doesn't possess a DNA mutation, the proliferation of cells in itself allows for an increase chance of spontaneous mutations, errors, leading to cancer. Since estrogen can cause cells to proliferate the development of antiestrogen drugs would prove beneficial in preventing cancer. Different types of chemically structured estrogen receptors occur in the human tissue allowing for drug selectivity. These drugs are referred to as selective estrogen receptor modulators, or SERMs, and can inhibit or stimulate estrogen. receptors in different tissues. Tomaxifen was first approved as a SERM for breast cancer

treatment in 1970 (1).

Figure 1- http://www.cancer.gov/cancertopics/understandingcancer/estrogenreceptors/Slide1 01/28/2005 accessed 3/01/2008

(1) John R. Lee, M.D. and Virginia Hopkins What your doctor may or may not tell you about Menopause The breakthrough book on natural progesterone. Warner Books 2004 (2) http://www.cancer.gov/cancertopics/understandingcancer/estrogenreceptors/Slide1 01/28/2005 accessed 3/01/2008

References: R. Michalides, A. Griekspoor, Rob Michalides, Alexander Griekspoor, Astrid Balkenende, Desiree Verwoerd, Lennert Janssen, Kees Jalink, Arno Floore, Arno Velds, Laura van 't Veer, and Jacques Neefjes. Tamoxifen resistance by a conformational arrest of the Estrogen receptor

_ after PKA activation in breast cancer. Cancer Cell 2004 vol.5 pp.597-605. Nicola Normann, Massimo Di Mai, Ermelinda De Maio, Antonella De Luca, Andrea de Matteis, Antonio Giordano, Francesco Perrone on behalf of the NCI-Naples Breast Cancer Group (2005) Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer. .Endocrine-Related Cancer 12 (4) 721-747. V. Craig Jordan, Susan Gapstur, Monica Morrow Selective Estrogen Receptor Modulation and Reduction in Risk of Breast Cancer, Osteoporosis, and Coronary Heart Disease. JNCI Journal of the National Cancer Institute 2001 93(19):1449-1457.

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