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    • br Acknowledgements We would like to

    2023-11-18


    Acknowledgements We would like to thank Dr. Thomas Blanpied, Sai Sachin Divakaruni, Dr. Helmut Kessels, Feline Lindhout, Dieudonnée van de Willige, and all members of the MacGillavry lab for discussions and critical reading of the manuscript. This work was supported by NWO (ALW-VENI 863.13.020, ALW-VIDI 171.029 and the Graduate Program of Quantitative Biology and Computational Life Sciences), the European Research Council (ERC-StG 716011), and a NARSAD Young Investigator Award (24995).
    Introduction Steroid hormone receptors have similar DNA-binding preferences, and their genomic binding is dependent on an overlapping set of additional transcription factors (Jozwik and Carroll, 2012, Robinson et al., 2011). Therefore, it is not surprising that the actions of one steroid hormone receptor can be altered by the induction of a different steroid hormone receptor. For example, progesterone receptor (PR) and Doxofylline receptor α (ER) often are co-expressed in breast cancer, and the induction of PR redirects ER genomic binding and reduces estrogen-driven growth (Mohammed et al., 2015, Singhal et al., 2016). Androgens enable breast cancer growth, and androgen receptor (AR) is important for ER genomic binding (D’Amato et al., 2016). Steroid hormones also are capable of compensating for one another. In prostate cancer, dexamethasone can confer resistance to anti-androgen therapy by activating glucocorticoid receptor (GR), which can substitute for AR in regulating transcription (Arora et al., 2013, Isikbay et al., 2014, Li et al., 2017). In the luminal androgen receptor subtype of breast cancer, AR compensates for the absence of ER by binding to similar genomic loci that are occupied by FOXA1 (Robinson et al., 2011). It is clear that steroid hormone receptors do not work in isolation and that they can perform overlapping functions. GR and ER have been shown to alter each other’s regulatory and phenotypic roles. GR expression is associated with good outcomes in ER-positive breast cancer and poor outcomes in ER-negative breast cancer (Pan et al., 2011), which is consistent with dexamethasone-blocking estrogen-induced growth in breast cancer cells (Zhou et al., 1989). When both steroid hormone receptors are active in breast cancer cells, GR affects the genomic interactions of ER (Miranda et al., 2013). GR activation alters chromatin accessibility, enabling ER to bind to a new set of genomic regions, a mechanism known as assisted loading (Voss et al., 2011). In addition, ER and GR have been shown to both cooperate with (Bolt et al., 2013) and compete (Karmakar et al., 2013, Meyer et al., 1989) for co-factors in breast cancer cells. GR also has been implicated in trans-repression of ER-regulated gene expression in breast cancer (Yang et al., 2017). Estrogens and corticosteroids can elicit opposite phenotypic effects in other tissues as well (Haynes et al., 2003, Lam et al., 1996, Terakawa et al., 1985), including the uterus (Gunin et al., 2001, Markaverich et al., 1981, Rabin et al., 1990, Rhen et al., 2003). Endometrial cancer is the most common gynecological cancer. Incidence, as well as mortality, associated with endometrial cancer is on the rise, and survival rates are significantly worse now than in the 1970s. Of endometrial cancers, 80%–90% are type I endometrioid tumors that express ER and are thought to be hormonally driven (Saso et al., 2011). Estrogen causes increased uterine growth and continued exposure can lead to endometrial hyperplasia (Yang et al., 2015). In contrast to the pro-growth role of ER in the uterus, GR reduces uterine growth and opposes phenotypic effects of estrogens in the uterus (Bever et al., 1956, Bitman and Cecil, 1967). Despite the opposing phenotypic roles, dexamethasone (Dex) and 17β-estradiol (E2), a GR and an ER agonist, respectively, produce similar gene expression changes in the normal uterus (Rhen et al., 2003). Although estrogen and corticosteroid signaling have been examined in the normal uterus, crosstalk between ER and GR has not been explored in the context of endometrial cancer on a genome-wide scale.