Endometrial safety: A key hurdle for selective estrogen receptor modulators in development
ABSTRACT Selective estrogen receptor modulators (SERMs) have the ability to provide mixed functional estrogen receptor (ER) agonist or antagonist activity, depending on the target tissue. Tamoxifen, the first SERM available for clinical use, is regarded as a highly effective agent for the prevention and treatment of breast cancer. However, tamoxifen exhibits ER agonist activity in the uterus and is associated with an increased risk of endometrial hyperplasia and malignancy. Endometrial safety has been an important consideration in the clinical development of SERMs, with improved benefit-risk profiles. Raloxifene, which is currently approved for the prevention and treatment of postmenopausal osteoporosis and for the prevention of breast cancer, seems to have neutral effects on the uterus. Promising results have been observed with the targeted development of newer and more tissue-specific SERMs, many of which are under investigation for postmenopausal osteoporosis. Of the newer SERMs in development, lasofoxifene has been shown to reduce fracture risk and decrease the incidence of breast cancer but has been associated with an increased incidence of vaginal bleeding, endometrial thickening, and endometrial polyps. Lasofoxifene and ospemifene have shown beneficial effects on the vaginal epithelium. Phase 3 clinical data have shown that bazedoxifene is effective in preventing and treating postmenopausal osteoporosis, without adverse effects on the endometrium or breast. Arzoxifene has been evaluated in phase 3 trials for postmenopausal osteoporosis and has been studied for the treatment of uterine malignancies but is no longer in clinical development. Further investigation of newer SERMs is warranted to more clearly define the endometrial safety of these agents.
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- "The lack of estrogen receptor α (ERα) expression in most type II tumors has led to the assumption that these tumors must be “estrogen-independent” and that treatment with antiestrogens (selective estrogen receptor modulators (SERMs) such as tamoxifen and Raloxifene, or pure antagonists/selective estrogen receptor modulators (SERDs) such as ICI182,780/fulvestrant) commonly used in breast cancer treatment, would be ineffectual, a conclusion largely substantiated in a number of clinical trials [5, 6]. In fact, prolonged treatment of breast cancer with SERMs such as tamoxifen leads to an increased incidence of endometrial cancer , particularly those of high-risk histologic types , resulting in significantly poorer overall survival . The effects of tamoxifen in the uterus have been ascribed to altered expression of nuclear coregulatory proteins in the endometrium compared to the breast, resulting in moderate agonist activity of tamoxifen in the uterus, compared to its antagonistic effects in the breast [10–13]. "
ABSTRACT: Endometrial carcinoma is the most common cancer of the female reproductive tract. GPER/GPR30 is a 7-transmembrane spanning G protein-coupled receptor that has been identified as the third estrogen receptor, in addition to ERα and ERβ. High GPER expression is predictive of poor survival in endometrial and ovarian cancer, but despite this, the estrogen-mediated signaling pathways and specific estrogen receptors involved in endometrial cancer remain unclear. Here, employing ERα-negative Hec50 endometrial cancer cells, we demonstrate that GPER mediates estrogen-stimulated activation of ERK and PI3K via matrix metalloproteinase activation and subsequent transactivation of the EGFR and that ER-targeted therapeutic agents (4-hydroxytamoxifen, ICI182,780/fulvestrant, and Raloxifene), the phytoestrogen genistein, and the "ERα-selective" agonist propylpyrazole triol also function as GPER agonists. Furthermore, xenograft tumors of Hec50 cells yield enhanced growth with G-1 and estrogen, the latter being inhibited by GPER-selective pharmacologic antagonism with G36. These results have important implications with respect to the use of putatively ER-selective ligands and particularly for the widespread long-term use of "ER-targeted" therapeutics. Moreover, our findings shed light on the potential mechanisms of SERM/SERD side effects reported in many clinical studies. Finally, our results provide the first demonstration that pharmacological inhibition of GPER activity in vivo prevents estrogen-mediated tumor growth.Obstetrics and Gynecology International 11/2013; 2013:472720. DOI:10.1155/2013/472720
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ABSTRACT: Breast cancer is one of the most common malignant tumours in women. More than a century ago it was noted that oophorectomy helps some but not all breast cancer patients. Further milestones in the development of endocrine treatment included the discovery of oestrogen receptors in breast tumours, introduction of tamoxifen, pharmacological ovarian ablation, and inhibitors of oestrogen biosynthesis in postmenopausal women. Each of these steps led to improvement in outcomes of breast cancer. However, despite the success of endocrine treatment, resistance remains an important clinical issue. There are no reliable markers for predicting endocrine resistance in ER-positive tumours and there is no rational targeted treatment of tumours, which do not respond (primary resistance) or progress after initial response (secondary resistance).
Article: The Role of Soy in Vegetarian Diets[Show abstract] [Hide abstract]
ABSTRACT: Soyfoods have long been prized among vegetarians for both their high protein content and versatility. Soybeans differ markedly in macronutrient content from other legumes, being much higher in fat and protein, and lower in carbohydrate. In recent years however, soyfoods and specific soybean constituents, especially isoflavones, have been the subject of an impressive amount of research. Nearly 2,000 soy-related papers are published annually. This research has focused primarily on the benefits that soyfoods may provide independent of their nutrient content. There is particular interest in the role that soyfoods have in reducing risk of heart disease, osteoporosis and certain forms of cancer. However, the estrogen-like effects of isoflavones observed in animal studies have also raised concerns about potential harmful effects of soyfood consumption. This review addresses questions related to soy and chronic disease risk, provides recommendations for optimal intakes, and discusses potential contraindications. As reviewed, the evidence indicates that, with the exception of those individuals allergic to soy protein, soyfoods can play a beneficial role in the diets of vegetarians. Concerns about adverse effects are not supported by the clinical or epidemiologic literature. Based on the soy intake associated with health benefits in the epidemiologic studies and the benefits noted in clinical trials, optimal adult soy intake would appear to be between two and four servings per day.Nutrients 08/2010; 2(8):855-88. DOI:10.3390/nu2080855 · 3.27 Impact Factor