Activation of mitogen- and stress-activated kinase 1 is required for proliferation of breast cancer cells in response to estrogens or progestins

摘要: Growth of breast cancers is often dependent on ovarian steroid hormones making the tumors responsive to antagonists hormone receptors. However, eventually become independent, raising need identify downstream targets for inhibition tumor growth. One possibility focus signaling mechanisms used by induce cancer cell proliferation. Here we report that mitogen- and stress-activated kinase 1 (MSK1) could be a potential druggable target. Using line T47D, show estrogens (E2) progestins activate MSK1, which forms complex with corresponding receptor. Inhibition MSK1 activity H89 or its depletion short hairpin RNAs (shRNAs) specifically abrogates proliferation in response E2 without affecting serum-induced required transition from G1- S-phase cycle compromises both estradiol- progestin-dependent induction genes. ChIP-seq experiments identified binding progesterone receptor-binding sites associated hormone-responsive recruitment epigenetically defined enhancer regions supports as chromatin remodeler hormone-dependent regulation gene transcription. In agreement this interpretation, expression histone H3 mutated at S10 eliminates hormonal effect relevant target Finally, E2- growth T47D cells xenografted immunodefficient mice inhibited indicating our findings are not restricted cultured cells, plays an important role more physiological context.