Lata Kusum, Mukherjee Tapan K
Department of Biology, Indian Institute of Science Education and Research (IISER) Mohali Sector 81, SAS Nagar, Manauli, 140306, Punjab, India.
Department of Biology, Indian Institute of Science Education and Research (IISER) Mohali Sector 81, SAS Nagar, Manauli, 140306, Punjab, India; Department of Biotechnology, Maharishi Markendeshwar University (A deemed University), Mullana, Haryana-133203, India.
Biochim Biophys Acta. 2014 Mar;1840(3):1083-91. doi: 10.1016/j.bbagen.2013.11.014. Epub 2013 Nov 16.
17α-ethinyl-estradiol (17α-EE), a synthetic estrogen is the world's most widely and commonly used orally bioactive estrogen. Currently, 17α-EE is in use in all formulations of contraceptive pills and is implicated in the complication of breast cancer. Receptor for advanced glycation end products (RAGE) is a cell surface immunoglobulin class of molecule. RAGE is involved in the complication of various cancers.
This study indicates that treatment of MCF-7 breast cancer cells with 17α-EE enhances the expression of estrogen receptor related receptor gamma (ERRγ), followed by enhanced level of oxidative stress and subsequent activation of the transcription factor, nuclear factor kappa-B (NF-кB), leading to increase in RAGE expression. RAGE thus expressed by 17α-EE treatment causes further enhancement of the oxidative stress which, in turn, activates expression of cell cycle protein cyclin D1 and subsequent induction of MCF-7 breast cancer cell proliferation. RAGE also enhanced phosphorylation of prosurvival protein AKT and increased expression of Bcl2, an antiapoptotic protein.
In MCF-7 breast cancer cells, 17α-EE-ERRγ interaction induces the expression of RAGE, which in turn, enhances the number of MCF-7 breast cancer cells through a multiprong action on the divergent molecules like cyclin D1, AKT and Bcl2.
This is the first report which explains the intermediate role of ERRγ in the 17α-EE dependent RAGE expression in MCF-7 breast cancer cells. This report for the first time explains that RAGE is important not only for MCF-7 breast cancer cell proliferation but also for its survival and anti-apoptotic activities.
17α-乙炔雌二醇（17α-EE）是一种合成雌激素，是世界上使用最广泛且常用的口服生物活性雌激素。目前，17α-EE存在于所有避孕药丸配方中，且与乳腺癌并发症有关。晚期糖基化终产物受体（RAGE）是一种细胞表面免疫球蛋白类分子。RAGE参与多种癌症的并发症。
本研究表明，用17α-EE处理MCF-7乳腺癌细胞可增强雌激素受体相关受体γ（ERRγ）的表达，随后氧化应激水平升高，转录因子核因子κB（NF-κB）被激活，导致RAGE表达增加。经17α-EE处理后如此表达的RAGE会进一步增强氧化应激，进而激活细胞周期蛋白D1的表达，随后诱导MCF-7乳腺癌细胞增殖。RAGE还增强了促生存蛋白AKT的磷酸化，并增加了抗凋亡蛋白Bcl2的表达。
在MCF-7乳腺癌细胞中，17α-EE与ERRγ的相互作用诱导RAGE的表达，而RAGE反过来通过对细胞周期蛋白D1、AKT和Bcl2等不同分子的多方面作用，增加MCF-7乳腺癌细胞的数量。
这是第一份解释ERRγ在MCF-7乳腺癌细胞中17α-EE依赖性RAGE表达中的中间作用的报告。本报告首次解释了RAGE不仅对MCF-7乳腺癌细胞增殖很重要，而且对其存活和抗凋亡活性也很重要。
