Estrogen and Cancer.
ABSTRACT Estrogen exhibits a broad spectrum of physiological functions ranging from regulation of the menstrual cycle and reproduction to modulation of bone density, brain function, and cholesterol mobilization. Despite the beneficial actions of endogenous estrogen, sustained exposure to exogenous estrogen is a well-established risk factor for various cancers. We summarize our current understanding of the molecular mechanisms of estrogen signaling in normal and cancer cells and discuss the major challenges to the existing antiestrogen therapy. Expected final online publication date for the Annual Review of Physiology Volume 75 is February 10, 2013. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
- SourceAvailable from: Anna Maria Musti
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- "Estrogens regulate critical signaling pathways involved in the control of cell proliferation and differentiation in reproductive and non-reproductive tissues (Liang and Shang, 2013). These steroids influence also the pathological processes of hormone-dependent tumors, like breast cancer, activating the estrogen receptor (ER)␣ and ER␤ which act as transcription factors binding to cognate the responsive elements located in the promoter regions of target genes (Ascenzi et al., 2006; Panno et al., 1996). "
ABSTRACT: The G protein-coupled receptor GPR30/GPER has been shown to mediate rapid effects of 17β-estradiol (E2) in diverse types of cancer cells. Here, we provide evidence for a novel crosstalk between GPER and the Notch signaling pathway in breast cancer cells and cancer-associated fibroblasts (CAFs). We show that E2 and the GPER selective ligand G-1 induce both the γ-secretase-dependent activation of Notch-1 and the expression of the Notch target gene Hes-1. These inductions are prevented by knocking down GPER or by using a dominant-negative mutant of the Notch transcriptional co-activator Master-mind like-1 (DN-MAML-1), hence suggesting the involvement of GPER in the Notch-dependent transcription. By performing chromatin-immunoprecipitation experiments and luciferase assays, we also demonstrate that E2 and G-1 induce the recruitment of the intracellular domain of Notch-1 (N1ICD) to the Hes-1 promoter and the transactivation of a Hes-1-reporter gene, respectively. Functionally, the E2 and G-1-induced migration of breast cancer cells and CAFs is abolished in presence of the γ-secretase inhibitor GSI or DN-MAML-1, which both inhibit the Notch signaling pathway. In addition, we demonstrate that E2 and G-1 prevent the expression of VE-Cadherin, while both compounds induce the expression of Snail, a Notch target gene acting as a repressor of cadherins expression. Notably, both GSI and DN-MAML-1 abolish the up-regulation of Snail-1 by E2 and G-1, whereas the use of GSI rescues VE-Cadherin expression. Taken together, our results prove the involvement of the Notch signaling pathway in mediating the effects of estrogenic GPER signaling in breast cancer cells and CAFs.The international journal of biochemistry & cell biology 11/2013; DOI:10.1016/j.biocel.2013.11.011 · 4.24 Impact Factor
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ABSTRACT: Several new coumarin and chromene prototype derivatives have been synthesised and evaluated for their ER alpha and ER beta selective activity. Coumarin prototype compounds 18 & 19 were found to be ER alpha selective and the most active, exhibiting potential antiproliferative activity against both ER + ve & ER -ve breast cancer cell lines. The surprise finding of the series, however, are the novel prototype III chromenes 45 & 46, with aroyl substitution at the 6th position. Both the compounds have shown potent antiproliferative activity against both the breast cancer cell lines, promote alkaline phosphatase activity, enhance osteoblast mineralization in vitro, significantly decrease ERE-ER alpha dependent transactivation and induce ER beta activity. This specific upregulation of ER beta isoform activity of compound 45 may be responsible for the antiosteoporotic activity at picomolar concentration. In addition, both the compounds were also devoid of any estrogenic activity, which correlates to their antiestrogenic behaviour in the two breast cancer cell lines. Assessment of selectivity using specific SiRNAs for ER alpha and ER beta revealed that most of the compounds showed ER alpha and ERb-mediated action, except compound 28, which showed selectivity to ER alpha only. Computational docking analysis of active compounds 18 and 45 was conducted to correlate the interaction with the two receptors and it was found that the docked conformations of the coumarin prototype, compound 18 at ER alpha and ER beta active sites were more or less superimposable on each other. However, the unique orientation of the aminoalkoxy side chain of novel chromene (prototype III) compound 45 in the ERb binding cavity may be responsible for its potential biological response.RSC Advances 11/2013; 4(17). DOI:10.1039/C3RA45749D · 3.84 Impact Factor
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ABSTRACT: Telomeres and telomerase are responsible for protection and maintenance of genomic stability of all eukaryotic cells. Several studies showed that one of the most distinguishing features of cancer cells is an increased expression and activity of telomerase, in contrast to somatic cells. This gives an opportunity for use of telomerase as a specific marker of cancer lesions or even as a molecular target. However, there are some questions concerning diagnostic specificity of this marker especially in the context of high proliferation potential of normal cells, such as the uterus and ovaries. The proliferation potential, however, decreases due to the menopause syndrome. Women's age and hormonal changes influence the functioning of many tissues, including alterations in telomerase activity of endometrial and ovarian cancer cells. The different characteristics of telomerase activity and telomere length in cells of postmenopausal women give an opportunity to utilize the telomeres and telomerase for the development of new cancer diagnostic tests and therapeutic methods. This work is aimed to summarize the information about the significance of telomeres and telomerase in the diagnosis and treatment of cancer in postmenopausal women.Menopausal Review 12/2013; 17(6):478-483. DOI:10.5114/pm.2013.39812 · 0.38 Impact Factor