Nuclear receptors outside the nucleus: extranuclear signalling by steroid receptors (original) (raw)

• Barkhem, T., Nilsson, S. & Gustafsson, J. A. Molecular mechanisms, physiological consequences and pharmacological implications of estrogen receptor action. Am. J. Pharmacogenomics 4, 19–28 (2004).
  CAS PubMed Google Scholar
• Selye, H. Stress and the general adaptation syndrome. Br. Med. J. 1, 1383–1392 (1950).
  CAS PubMed PubMed Central Google Scholar
• Lykissas, E. D., Kourounakis, P. & Selye, H. Hepatic intracellular distribution of pregnenolone-16α-carbonitrile and its influence on adenyl cyclase activity in rat liver cells. Res. Commun. Chem. Pathol. Pharmacol. 19, 173–176 (1978).
  CAS PubMed Google Scholar
• Spaziani, E. & Szego, C. M. Early effects of estradiol and cortisol on water and electrolyte shifts in the uterus of the immature rat. Am. J. Physiol. 197, 355–359 (1959).
  CAS PubMed Google Scholar
• Szego, C. M. & Davis, J. S. Adenosine 3′,5′-monophosphate in rat uterus: acute elevation by estrogen. Proc. Natl Acad. Sci. USA 58, 1711–1718 (1967).
  CAS PubMed Google Scholar
• Pietras, R. J. & Szego, C. M. Specific binding sites for oestrogen at the outer surfaces of isolated endometrial cells. Nature 265, 69–72 (1977).Demonstrates clearly for the first time the presence of steroid-binding sites at the plasma membrane.
  CAS PubMed Google Scholar
• Wang, Z. Y., Seto, H., Fujioka, S., Yoshida, S. & Chory, J. BRI1 is a critical component of a plasma-membrane receptor for plant steroids. Nature 410, 380–383 (2001).
  CAS PubMed Google Scholar
• Hammes, S. R. & Levin, E. R. Extranuclear steroid receptors: nature and actions. Endocr. Rev. 28, 726–741 (2007).
  CAS PubMed Google Scholar
• Sen, A. et al. Paxillin mediates extranuclear and intranuclear signaling in prostate cancer proliferation. J. Clin. Invest. 122, 2469–2481 (2012).Provides the first demonstration of collaborative extranuclear and nuclear AR signalling.
  CAS PubMed PubMed Central Google Scholar
• Sen, A. et al. Paxillin regulates androgen- and epidermal growth factor-induced MAPK signaling and cell proliferation in prostate cancer cells. J. Biol. Chem. 285, 28787–28795 (2010).
  CAS PubMed PubMed Central Google Scholar
• Migliaccio, A. et al. Steroid-induced androgen receptor-oestradiol receptor β-Src complex triggers prostate cancer cell proliferation. EMBO J. 19, 5406–5417 (2000).
  CAS PubMed PubMed Central Google Scholar
• Migliaccio, A. et al. Activation of the Src/p21ras/Erk pathway by progesterone receptor via cross-talk with estrogen receptor. EMBO J. 17, 2008–2018 (1998).
  CAS PubMed PubMed Central Google Scholar
• Daniel, A. R. et al. Progesterone receptor-B enhances estrogen responsiveness of breast cancer cells via scaffolding PELP1- and estrogen receptor-containing transcription complexes. Oncogene 34, 506–515 (2015).
  CAS PubMed Google Scholar
• McNamara, K. M., Moore, N. L., Hickey, T. E., Sasano, H. & Tilley, W. D. Complexities of androgen receptor signalling in breast cancer. Endocr. Relat. Cancer 21, T161–T181 (2014).
  CAS PubMed Google Scholar
• Simons, S. S. Jr, Edwards, D. P. & Kumar, R. Minireview: dynamic structures of nuclear hormone receptors: new promises and challenges. Mol. Endocrinol. 28, 173–182 (2014).
  PubMed Google Scholar
• Burns, K. A., Li, Y., Arao, Y., Petrovich, R. M. & Korach, K. S. Selective mutations in estrogen receptor α D-domain alters nuclear translocation and non-estrogen response element gene regulatory mechanisms. J. Biol. Chem. 286, 12640–12649 (2011).
  CAS PubMed PubMed Central Google Scholar
• Shiau, A. K. et al. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 95, 927–937 (1998).
  CAS PubMed Google Scholar
• Lubahn, D. B. et al. Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proc. Natl Acad. Sci. USA 90, 11162–11166 (1993).
  CAS PubMed Google Scholar
• Lydon, J. P. et al. Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev. 9, 2266–2278 (1995).
  CAS PubMed Google Scholar
• Pappas, T. C., Gametchu, B. & Watson, C. S. Membrane estrogen receptors identified by multiple antibody labeling and impeded-ligand binding. FASEB J. 9, 404–410 (1995).
  CAS PubMed Google Scholar
• Norfleet, A. M., Thomas, M. L., Gametchu, B. & Watson, C. S. Estrogen receptor-α detected on the plasma membrane of aldehyde-fixed GH3/B6/F10 rat pituitary tumor cells by enzyme-linked immunocytochemistry. Endocrinology 140, 3805–3814 (1999).
  CAS PubMed Google Scholar
• Razandi, M., Pedram, A., Greene, G. L. & Levin, E. R. Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: studies of ERα and ERβ expressed in Chinese hamster ovary cells. Mol. Endocrinol. 13, 307–319 (1999).
  CAS PubMed Google Scholar
• Pedram, A., Razandi, M. & Levin, E. R. Nature of functional estrogen receptors at the plasma membrane. Mol. Endocrinol. 20, 1996–2009 (2006).
  CAS PubMed Google Scholar
• Kousteni, S. et al. Reversal of bone loss in mice by nongenotropic signaling of sex steroids. Science 298, 843–846 (2002).Reveals that transcription-independent oestrogen signalling is important for normal bone formation.
  CAS PubMed Google Scholar
• Li, L., Haynes, M. P. & Bender, J. R. Plasma membrane localization and function of the estrogen receptor α variant (ER46) in human endothelial cells. Proc. Natl Acad. Sci. USA 100, 4807–4812 (2003).
  CAS PubMed Google Scholar
• Wang, Z. et al. A variant of estrogen receptor-α, hER-α36: transduction of estrogen- and antiestrogen-dependent membrane-initiated mitogenic signaling. Proc. Natl Acad. Sci. USA 103, 9063–9068 (2006).
  CAS PubMed Google Scholar
• Nilsson, S. et al. Mechanisms of estrogen action. Physiol. Rev. 81, 1535–1565 (2001).
  CAS PubMed Google Scholar
• Flouriot, G., Griffin, C., Kenealy, M., Sonntag-Buck, V. & Gannon, F. Differentially expressed messenger RNA isoforms of the human estrogen receptor-α gene are generated by alternative splicing and promoter usage. Mol. Endocrinol. 12, 1939–1954 (1998).
  CAS PubMed Google Scholar
• Pedram, A. et al. A conserved mechanism for steroid receptor translocation to the plasma membrane. J. Biol. Chem. 282, 22278–22288 (2007).
  CAS PubMed Google Scholar
• Lutz, L. B. et al. Evidence that androgens are the primary steroids produced by Xenopus laevis ovaries and may signal through the classical androgen receptor to promote oocyte maturation. Proc. Natl Acad. Sci. USA 98, 13728–13733 (2001).
  CAS PubMed Google Scholar
• Lutz, L. B., Kim, B., Jahani, D. & Hammes, S. R. G protein βγ subunits inhibit nongenomic progesterone-induced signaling and maturation in Xenopus laevis oocytes. Evidence for a release of inhibition mechanism for cell cycle progression. J. Biol. Chem. 275, 41512–41520 (2000).Shows that androgens modulate G protein signalling at the cell membrane.
  CAS PubMed Google Scholar
• Evaul, K., Jamnongjit, M., Bhagavath, B. & Hammes, S. R. Testosterone and progesterone rapidly attenuate plasma membrane Gβγ-mediated signaling in Xenopus laevis oocytes by signaling through classical steroid receptors. Mol. Endocrinol. 21, 186–196 (2007).
  CAS PubMed Google Scholar
• Sen, A. & Hammes, S. R. Granulosa cell-specific androgen receptors are critical regulators of ovarian development and function. Mol. Endocrinol. 24, 1393–1403 (2010).
  CAS PubMed PubMed Central Google Scholar
• Sen, A. et al. Androgens regulate ovarian follicular development by increasing follicle stimulating hormone receptor and microRNA-125b expression. Proc. Natl Acad. Sci. USA 111, 3008–3013 (2014).
  CAS PubMed Google Scholar
• Ballare, C. et al. Two domains of the progesterone receptor interact with the estrogen receptor and are required for progesterone activation of the c-Src/Erk pathway in mammalian cells. Mol. Cell. Biol. 23, 1994–2008 (2003).
  CAS PubMed PubMed Central Google Scholar
• Boonyaratanakornkit, V. et al. Progesterone receptor contains a proline-rich motif that directly interacts with SH3 domains and activates c-Src family tyrosine kinases. Mol. Cell 8, 269–280 (2001).
  CAS PubMed Google Scholar
• Nemere, I. et al. Ribozyme knockdown functionally links a 1,25(OH)2D3 membrane binding protein (1,25D3-MARRS) and phosphate uptake in intestinal cells. Proc. Natl Acad. Sci. USA 101, 7392–7397 (2004).
  CAS PubMed Google Scholar
• Mizwicki, M. T. & Norman, A. W. The vitamin D sterol-vitamin D receptor ensemble model offers unique insights into both genomic and rapid-response signaling. Sci. Signal. 2, re4 (2009).
  PubMed Google Scholar
• Kalyanaraman, H. et al. Nongenomic thyroid hormone signaling occurs through a plasma membrane-localized receptor. Sci. Signal. 7, ra48 (2014).Provides the first description of a membrane-localized, truncated form of THRα.
  PubMed PubMed Central Google Scholar
• Martin, N. P. et al. A rapid cytoplasmic mechanism for PI3 kinase regulation by the nuclear thyroid hormone receptor, TRβ, and genetic evidence for its role in the maturation of mouse hippocampal synapses in vivo. Endocrinology 155, 3713–3724 (2014).Describes the functional effects of rapid signalling by extranuclear THRβ.
  PubMed PubMed Central Google Scholar
• Filardo, E. J., Quinn, J. A., Bland, K. I. & Frackelton, A. R. Jr. Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via _trans_-activation of the epidermal growth factor receptor through release of HB-EGF. Mol. Endocrinol. 14, 1649–1660 (2000).
  CAS PubMed Google Scholar
• Thomas, P., Pang, Y., Filardo, E. J. & Dong, J. Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells. Endocrinology 146, 624–632 (2005).
  CAS PubMed Google Scholar
• Revankar, C. M., Cimino, D. F., Sklar, L. A., Arterburn, J. B. & Prossnitz, E. R. A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science 307, 1625–1630 (2005).
  CAS PubMed Google Scholar
• Otto, C. et al. G protein-coupled receptor 30 localizes to the endoplasmic reticulum and is not activated by estradiol. Endocrinology 149, 4846–4856 (2008).
  CAS PubMed Google Scholar
• Isensee, J. et al. Expression pattern of G protein-coupled receptor 30 in LacZ reporter mice. Endocrinology 150, 1722–1730 (2009).
  CAS PubMed Google Scholar
• Otto, C. et al. GPR30 does not mediate estrogenic responses in reproductive organs in mice. Biol. Reprod. 80, 34–41 (2009).
  CAS PubMed Google Scholar
• Albanito, L. et al. G protein-coupled receptor 30 (GPR30) mediates gene expression changes and growth response to 17β-estradiol and selective GPR30 ligand G-1 in ovarian cancer cells. Cancer Res. 67, 1859–1866 (2007).
  CAS PubMed Google Scholar
• Madak-Erdogan, Z. et al. Nuclear and extranuclear pathway inputs in the regulation of global gene expression by estrogen receptors. Mol. Endocrinol. 22, 2116–2127 (2008).
  CAS PubMed PubMed Central Google Scholar
• Takabe, K. et al. Estradiol induces export of sphingosine 1-phosphate from breast cancer cells via ABCC1 and ABCG2. J. Biol. Chem. 285, 10477–10486 (2010).
  CAS PubMed PubMed Central Google Scholar
• Gaudet, H. M., Cheng, S. B., Christensen, E. M. & Filardo, E. J. The G-protein coupled estrogen receptor, GPER: the inside and inside-out story. Mol. Cell. Endocrinol. 3, 207–219 (2015).Reviews recent research on the functions of GPER1.
  Google Scholar
• Engmann, L., Losel, R., Wehling, M. & Peluso, J. J. Progesterone regulation of human granulosa/luteal cell viability by an RU486-independent mechanism. J. Clin. Endocrinol. Metab. 91, 4962–4968 (2006).
  CAS PubMed Google Scholar
• Friel, A. M. et al. Progesterone receptor membrane component 1 deficiency attenuates growth while promoting chemosensitivity of human endometrial xenograft tumors. Cancer Lett. 356, 434–442 (2015).
  CAS PubMed Google Scholar
• Li, X. et al. Progesterone receptor membrane component-1 regulates hepcidin biosynthesis. J. Clin. Invest. 126, 389–401 (2016).Demonstrates the importance of PGRMC1 for the regulation of iron metabolism.
  PubMed Google Scholar
• Zhu, Y., Bond, J. & Thomas, P. Identification, classification, and partial characterization of genes in humans and other vertebrates homologous to a fish membrane progestin receptor. Proc. Natl Acad. Sci. USA 100, 2237–2242 (2003).
  CAS PubMed Google Scholar
• Zhu, Y., Rice, C. D., Pang, Y., Pace, M. & Thomas, P. Cloning, expression, and characterization of a membrane progestin receptor and evidence it is an intermediary in meiotic maturation of fish oocytes. Proc. Natl Acad. Sci. USA 100, 2231–2236 (2003).
  CAS PubMed Google Scholar
• Sleiter, N. et al. Progesterone receptor A (PRA) and PRB-independent effects of progesterone on gonadotropin-releasing hormone release. Endocrinology 150, 3833–3844 (2009).
  CAS PubMed PubMed Central Google Scholar
• Pi, M. et al. Structural and functional evidence for testosterone activation of GPRC6A in peripheral tissues. Mol. Endocrinol. 29, 1759–1773 (2015).
  CAS PubMed PubMed Central Google Scholar
• Pi, M., Parrill, A. L. & Quarles, L. D. GPRC6A mediates the non-genomic effects of steroids. J. Biol. Chem. 285, 39953–39964 (2010).
  CAS PubMed PubMed Central Google Scholar
• Razandi, M., Pedram, A., Merchenthaler, I., Greene, G. L. & Levin, E. R. Plasma membrane estrogen receptors exist and functions as dimers. Mol. Endocrinol. 18, 2854–2865 (2004).
  CAS PubMed Google Scholar
• Pedram, A., Razandi, M., Deschenes, R. J. & Levin, E. R. DHHC-7 and -21 are palmitoylacyltransferases for sex steroid receptors. Mol. Biol. Cell 23, 188–199 (2012).
  CAS PubMed PubMed Central Google Scholar
• Galluzzo, P., Caiazza, F., Moreno, S. & Marino, M. Role of ERβ palmitoylation in the inhibition of human colon cancer cell proliferation. Endocr. Relat. Cancer 14, 153–167 (2007).
  CAS PubMed Google Scholar
• Acconcia, F. et al. Palmitoylation-dependent estrogen receptor α membrane localization: regulation by 17β-estradiol. Mol. Biol. Cell 16, 231–237 (2005).
  CAS PubMed PubMed Central Google Scholar
• Razandi, M., Pedram, A. & Levin, E. R. Heat shock protein 27 is required for sex steroid receptor trafficking to and functioning at the plasma membrane. Mol. Cell. Biol. 30, 3249–3261 (2010).
  CAS PubMed PubMed Central Google Scholar
• Peffer, M. E. et al. Caveolin-1 regulates genomic action of the glucocorticoid receptor in neural stem cells. Mol. Cell. Biol. 34, 2611–2623 (2014).
  PubMed PubMed Central Google Scholar
• Razandi, M., Oh, P., Pedram, A., Schnitzer, J. & Levin, E. R. ERs associate with and regulate the production of caveolin: implications for signaling and cellular actions. Mol. Endocrinol. 16, 100–115 (2002).
  CAS PubMed Google Scholar
• Kumar, P. et al. Direct interactions with Gαi and Gβγ mediate nongenomic signaling by estrogen receptor α. Mol. Endocrinol. 21, 1370–1380 (2007).
  CAS PubMed Google Scholar
• Razandi, M., Pedram, A., Park, S. T. & Levin, E. R. Proximal events in signaling by plasma membrane estrogen receptors. J. Biol. Chem. 278, 2701–2712 (2003).
  CAS PubMed Google Scholar
• Song, R. X. et al. The role of Shc and insulin-like growth factor 1 receptor in mediating the translocation of estrogen receptor α to the plasma membrane. Proc. Natl Acad. Sci. USA 101, 2076–2081 (2004).
  CAS PubMed Google Scholar
• Galluzzo, P., Ascenzi, P., Bulzomi, P. & Marino, M. The nutritional flavanone naringenin triggers antiestrogenic effects by regulating estrogen receptor α-palmitoylation. Endocrinology 149, 2567–2575 (2008).
  CAS PubMed Google Scholar
• Totta, P., Pesiri, V., Marino, M. & Acconcia, F. Lysosomal function is involved in 17β-estradiol-induced estrogen receptor α degradation and cell proliferation. PLoS ONE 9, e94880 (2014).
  PubMed PubMed Central Google Scholar
• Faivre, E. J. & Lange, C. A. Progesterone receptors upregulate Wnt-1 to induce epidermal growth factor receptor transactivation and c-Src-dependent sustained activation of Erk1/2 mitogen-activated protein kinase in breast cancer cells. Mol. Cell. Biol. 27, 466–480 (2007).
  CAS PubMed Google Scholar
• Thomas, W. & Harvey, B. J. Mechanisms underlying rapid aldosterone effects in the kidney. Annu. Rev. Physiol. 73, 335–357 (2011).
  CAS PubMed Google Scholar
• Grossmann, C., Freudinger, R., Mildenberger, S., Husse, B. & Gekle, M. EF domains are sufficient for nongenomic mineralocorticoid receptor actions. J. Biol. Chem. 283, 7109–7116 (2008).
  CAS PubMed Google Scholar
• Le Moellic, C. et al. Early nongenomic events in aldosterone action in renal collecting duct cells: PKCα activation, mineralocorticoid receptor phosphorylation, and cross-talk with the genomic response. J. Am. Soc. Nephrol. 15, 1145–1160 (2004).
  CAS PubMed Google Scholar
• Weigel, N. L. & Moore, N. L. Kinases and protein phosphorylation as regulators of steroid hormone action. Nucl. Recept. Signal. 5, e005 (2007).
  PubMed PubMed Central Google Scholar
• York, B. et al. Reprogramming the posttranslational code of SRC-3 confers a switch in mammalian systems biology. Proc. Natl Acad. Sci. USA 107, 11122–11127 (2010).
  CAS PubMed Google Scholar
• Zheng, F. F., Wu, R. C., Smith, C. L. & O'Malley, B. W. Rapid estrogen-induced phosphorylation of the SRC-3 coactivator occurs in an extranuclear complex containing estrogen receptor. Mol. Cell. Biol. 25, 8273–8284 (2005).
  CAS PubMed PubMed Central Google Scholar
• Jonas, B. A. & Privalsky, M. L. SMRT and N-CoR corepressors are regulated by distinct kinase signaling pathways. J. Biol. Chem. 279, 54676–54686 (2004).
  CAS PubMed PubMed Central Google Scholar
• Trevino, L. S. & Weigel, N. L. Phosphorylation: a fundamental regulator of steroid receptor action. Trends Endocrinol. Metab. 24, 515–524 (2013).
  CAS PubMed PubMed Central Google Scholar
• Wong, W. P. et al. Extranuclear estrogen receptor-α stimulates NeuroD1 binding to the insulin promoter and favors insulin synthesis. Proc. Natl Acad. Sci. USA 107, 13057–13062 (2010).
  CAS PubMed Google Scholar
• Vazquez-Martin, A. et al. Reprogramming of non-genomic estrogen signaling by the stemness factor SOX2 enhances the tumor-initiating capacity of breast cancer cells. Cell Cycle 12, 3471–3477 (2013).
  CAS PubMed PubMed Central Google Scholar
• Vares, G. et al. Progesterone generates cancer stem cells through membrane progesterone receptor-triggered signaling in basal-like human mammary cells. Cancer Lett. 362, 167–173 (2015).
  CAS PubMed Google Scholar
• Pedram, A., Razandi, M., Blumberg, B. & Levin, E. R. Membrane and nuclear estrogen receptor α collaborate to suppress adipogenesis but not triglyceride content. FASEB J. 30, 230–240 (2016).Indicates the collaboration of membrane and nuclear ERα to suppress bone marrow-derived progenitor cells from committing to the adipocyte lineage.
  CAS PubMed Google Scholar
• Pedram, A. et al. Estrogen reduces lipid content in the liver exclusively from membrane receptor signaling. Sci. Signal. 6, ra36 (2013).Provides in vivo evidence that important lipid-suppressing functions of oestrogen are dependent entirely on membrane ERα signalling.
  PubMed Google Scholar
• Tiano, J. P. et al. Estrogen receptor activation reduces lipid synthesis in pancreatic islets and prevents β cell failure in rodent models of type 2 diabetes. J. Clin. Invest. 121, 3331–3342 (2011).
  CAS PubMed PubMed Central Google Scholar
• Tiano, J. P. & Mauvais-Jarvis, F. Molecular mechanisms of estrogen receptors' suppression of lipogenesis in pancreatic β-cells. Endocrinology 153, 2997–3005 (2012).
  CAS PubMed PubMed Central Google Scholar
• Bredfeldt, T. G. et al. Xenoestrogen-induced regulation of EZH2 and histone methylation via estrogen receptor signaling to PI3K/AKT. Mol. Endocrinol. 24, 993–1006 (2010).
  CAS PubMed PubMed Central Google Scholar
• Pedram, A., Razandi, M., Lewis, M., Hammes, S. & Levin, E. R. Membrane-localized estrogen receptor α is required for normal organ development and function. Dev. Cell 29, 482–490 (2014).
  CAS PubMed PubMed Central Google Scholar
• Pedram, A. et al. Estrogen regulates histone deacetylases to prevent cardiac hypertrophy. Mol. Biol. Cell 24, 3805–3818 (2013).
  PubMed PubMed Central Google Scholar
• Masui, K., Cavenee, W. K. & Mischel, P. S. mTORC2 in the center of cancer metabolic reprogramming. Trends Endocrinol. Metab. 25, 364–373 (2014).
  CAS PubMed PubMed Central Google Scholar
• Bhatt, S., Xiao, Z., Meng, Z. & Katzenellenbogen, B. S. Phosphorylation by p38 mitogen-activated protein kinase promotes estrogen receptor α turnover and functional activity via the SCF(Skp2) proteasomal complex. Mol. Cell. Biol. 32, 1928–1943 (2012).
  CAS PubMed PubMed Central Google Scholar
• Reid, G. et al. Cyclic, proteasome-mediated turnover of unliganded and liganded ERα on responsive promoters is an integral feature of estrogen signaling. Mol. Cell 11, 695–707 (2003).
  CAS PubMed Google Scholar
• Gutierrez-Mecinas, M. et al. Long-lasting behavioral responses to stress involve a direct interaction of glucocorticoid receptors with ERK1/2–MSK1–Elk-1 signaling. Proc. Natl Acad. Sci. USA 108, 13806–13811 (2011).
  CAS PubMed Google Scholar
• Nahar, J. et al. Rapid nongenomic glucocorticoid actions in male mouse hypothalamic neuroendocrine cells are dependent on the nuclear glucocorticoid receptor. Endocrinology 156, 2831–2842 (2015).
  CAS PubMed PubMed Central Google Scholar
• Pedram, A. et al. Developmental phenotype of a membrane only estrogen receptor α (MOER) mouse. J. Biol. Chem. 284, 3488–3495 (2009).
  CAS PubMed PubMed Central Google Scholar
• Mauvais-Jarvis, F., Clegg, D. J. & Hevener, A. L. The role of estrogens in control of energy balance and glucose homeostasis. Endocr. Rev. 34, 309–338 (2013).
  CAS PubMed PubMed Central Google Scholar
• Soriano, S. et al. Rapid regulation of KATP channel activity by 17β-estradiol in pancreatic β-cells involves the estrogen receptor β and the atrial natriuretic peptide receptor. Mol. Endocrinol. 23, 1973–1982 (2009).
  CAS PubMed PubMed Central Google Scholar
• O'Mahony, F., Razandi, M., Pedram, A., Harvey, B. J. & Levin, E. R. Estrogen modulates metabolic pathway adaptation to available glucose in breast cancer cells. Mol. Endocrinol. 26, 2058–2070 (2012).
  CAS PubMed PubMed Central Google Scholar
• Fierz, Y., Novosyadlyy, R., Vijayakumar, A., Yakar, S. & LeRoith, D. Insulin-sensitizing therapy attenuates type 2 diabetes-mediated mammary tumor progression. Diabetes 59, 686–693 (2010).
  CAS PubMed Google Scholar
• Novosyadlyy, R. et al. Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type 2 diabetes. Cancer Res. 70, 741–751 (2010).
  CAS PubMed PubMed Central Google Scholar
• Pedram, A., Razandi, M., Aitkenhead, M. & Levin, E. R. Estrogen inhibits cardiomyocyte hypertrophy in vitro. Antagonism of calcineurin-related hypertrophy through induction of MCIP1. J. Biol. Chem. 280, 26339–26348 (2005).
  CAS PubMed PubMed Central Google Scholar
• Pedram, A., Razandi, M., O'Mahony, F., Lubahn, D. & Levin, E. R. Estrogen receptor-β prevents cardiac fibrosis. Mol. Endocrinol. 24, 2152–2165 (2010).
  CAS PubMed PubMed Central Google Scholar
• Chen, Z. et al. Estrogen receptor α mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. J. Clin. Invest. 103, 401–406 (1999).
  CAS PubMed PubMed Central Google Scholar
• Adlanmerini, M. et al. Mutation of the palmitoylation site of estrogen receptor α in vivo reveals tissue-specific roles for membrane versus nuclear actions. Proc. Natl Acad. Sci. USA 111, E283–E290 (2014).
  CAS PubMed Google Scholar
• Umetani, M. et al. 27-Hydroxycholesterol is an endogenous SERM that inhibits the cardiovascular effects of estrogen. Nat. Med. 13, 1185–1192 (2007).
  CAS PubMed Google Scholar
• Umetani, M. & Shaul, P. W. 27-Hydroxycholesterol: the first identified endogenous SERM. Trends Endocrinol. Metab. 22, 130–135 (2011).
  CAS PubMed PubMed Central Google Scholar
• Wu, Q. et al. 27-Hydroxycholesterol promotes cell-autonomous, ER-positive breast cancer growth. Cell Rep. 5, 637–645 (2013).Provides the first report of breast tumour-produced 27HC and a potential role in aromatase-inhibitor therapy for this malignancy.
  CAS PubMed PubMed Central Google Scholar
• Ishikawa, T. et al. LXRβ/estrogen receptor-α signaling in lipid rafts preserves endothelial integrity. J. Clin. Invest. 123, 3488–3497 (2013).
  CAS PubMed PubMed Central Google Scholar
• Lefterova, M. I., Haakonsson, A. K., Lazar, M. A. & Mandrup, S. PPARγ and the global map of adipogenesis and beyond. Trends Endocrinol. Metab. 25, 293–302 (2014).
  CAS PubMed PubMed Central Google Scholar
• Choi, J., Park, S. & Sockanathan, S. Activated retinoid receptors are required for the migration and fate maintenance of subsets of cortical neurons. Development 141, 1151–1160 (2014).
  CAS PubMed Google Scholar
• Lee, C. T. et al. The nuclear orphan receptor COUP-TFII is required for limb and skeletal muscle development. Mol. Cell. Biol. 24, 10835–10843 (2004).
  CAS PubMed PubMed Central Google Scholar
• Noguchi, K. K., Lau, K., Smith, D. J., Swiney, B. S. & Farber, N. B. Glucocorticoid receptor stimulation and the regulation of neonatal cerebellar neural progenitor cell apoptosis. Neurobiol. Dis. 43, 356–363 (2011).
  CAS PubMed PubMed Central Google Scholar
• Atwood, C. S. et al. Progesterone induces side-branching of the ductal epithelium in the mammary glands of peripubertal mice. J. Endocrinol. 167, 39–52 (2000).
  CAS PubMed Google Scholar
• Brisken, C. & O'Malley, B. Hormone action in the mammary gland. Cold Spring Harb. Perspect. Biol. 2, a003178 (2010).
  CAS PubMed PubMed Central Google Scholar
• Han, S. J. et al. Estrogen receptor β modulates apoptosis complexes and the inflammasome to drive the pathogenesis of endometriosis. Cell 163, 960–974 (2015).
  CAS PubMed PubMed Central Google Scholar
• Pedram, A., Razandi, M., Wallace, D. C. & Levin, E. R. Functional estrogen receptors in the mitochondria of breast cancer cells. Mol. Biol. Cell 17, 2125–2137 (2006).
  CAS PubMed PubMed Central Google Scholar
• Adzic, M. et al. Brain region- and sex-specific modulation of mitochondrial glucocorticoid receptor phosphorylation in fluoxetine treated stressed rats: effects on energy metabolism. Psychoneuroendocrinology 38, 2914–2924 (2013).
  CAS PubMed Google Scholar
• Lee, S. R. et al. Glucocorticoids and their receptors: insights into specific roles in mitochondria. Prog. Biophys Mol. Biol. 112, 44–54 (2013).Highlights the functions of GR in mitochondria.
  CAS PubMed Google Scholar
• Simoes, D. C. et al. Glucocorticoid and estrogen receptors are reduced in mitochondria of lung epithelial cells in asthma. PLoS ONE 7, e39183 (2012).
  CAS PubMed PubMed Central Google Scholar
• Razandi, M., Pedram, A., Jordan, V. C., Fuqua, S. & Levin, E. R. Tamoxifen regulates cell fate through mitochondrial estrogen receptor β in breast cancer. Oncogene 32, 3274–3285 (2013).
  CAS PubMed Google Scholar