Does the orphan nuclear receptor ERRγ link cholesterol synthesis to endocrine therapy resistance? Free

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Estrogen receptors alpha and beta (ERα, ERβ) play a central role in the etiology of breast cancer and drive our approach to therapeutic intervention. While these and many other nuclear receptors (NRs) are responsive to specific ligands, there are orphan NRs for which no ligand has yet been identified. The function of these receptors in breast cancer biology is often poorly understood. Estrogen-related receptor gamma (ERRγ) is one orphan NR with structural similarities to ERα and ERβ. In addition to its ability to transactivate classical and imperfect estrogen response elements (EREs), ERRγ is a potent activator of transcription from steroidogenic factor-1 (SF-1) response elements (SF-1REs). Many genes regulated by SF-1REs control key aspects of cholesterol and fatty acid synthesis, important not only for generation of the plasma membrane but also for the synthesis of steroid hormones. Consequently, upregulation of ERRγ may increase the cholesterol production capacity of breast cancer cells poised to proliferate in response to estrogen. This has the potential to promote the development of hormone-refractory breast cancer, and is also likely to attenuate the therapeutic effectiveness of antiestrogens designed to inhibit ER function. We have found that ERRγ is upregulated 4-fold (p=0.015) in LCCTam cells, a multi-antiestrogen resistant variant of the ER-positive SUM44 breast cancer cell line, a model of invasive lobular carcinoma. ERRγ overexpression is accompanied by a significant increase in basal and estrogen-stimulated ERE transcriptional activity, and siRNA-mediated knockdown of ERRγ in LCCTam cells completely restores sensitivity to both 4-hydroxytamoxifen and Fulvestrant (p=0.03). Furthermore, LCCTam cells produce greater levels of cholesterol than SUM44, and we have found that the expression of three genes with established connections to cholesterol and steroid hormone synthesis is significantly increased in LCCTam: HMG-CoA synthase 2 (HMGCS2, 9.6-fold), GATA binding protein 4 (GATA4, 4.4-fold), and sterol regulatory element binding transcription factor 1 (SREBF1, 1.8-fold). Together these data suggest that ERRγ may affect endocrine resistance in the LCCTam breast cancer model by regulating cholesterol production.