This complex bidirectional regulation is an emerging and exciting field of study that is critical to pursue, as hormone-dependent cancers are frequently treated with DNA damaging regimens, and new clinical data is emerging using agents that target certain DDR components that possess NR-regulatory capabilities. While the observations outlined herein are provocative, a number of key questions remain. include decreased proliferation, increased apoptosis, and reduced tumor formation in a heterozygous murine mammary model . In sum, estrogen and progesterone signaling promote Adoprazine (SLV313) the activity of p53, indicating that female sex hormones have the potential to positively regulate tumor suppressor function. Conversely, male sex hormones have been ITM2B implicated in diminishing p53 function. Androgen signaling through the androgen receptor (AR) inhibits p53 function in models of hepatocellular carcinoma (HCC) , leading to reduced apoptosis and increased proliferation. It has been reported that dexamethasone (a glucocorticoid receptor agonist) treatment when in combination with the chemotherapy drug cisplatin (CDDP) reduces efficacy of treatment Adoprazine (SLV313) in models of non-small cell lung cancer (NSCLC) via attenuation of p53 activity . The comparable actions of androgens and glucocorticoids around the function of p53 may be attributed to the knowledge that AR and glucocorticoid receptor (GR) are more evolutionarily related to each other than to the ER , suggesting an evolutionary pressure for this dichotomous regulation of p53 function. Although PR and AR are more evolutionarily related than GR and AR, suggesting that ER function may be dominant to PR function with respect to p53 regulation. Additionally, the studies of negative regulation by AR and GR were conducted in tissues not typically considered as hormone-responsive (e.g. liver and lung) [40, 41]. Furthermore, glucocorticoids are often used in concert with DNA damaging regimens to reduce side effects of chemotherapy . Therefore, the negative impact of GR signaling on p53 activity may have broader implications around the strength and duration of a therapeutic response to chemotherapy in any tumor type, and not simply restricted to hormone-dependent malignancies. Taken together, these data Adoprazine (SLV313) indicate that ER and progesterone receptor (PR) signaling positively regulate p53, while AR and GR signaling negatively regulate p53 function. While it is usually unclear what the implications of these regulatory events are for tumor phenotypes and/or malignant progression, these functional interactions may be relevant when combining hormone therapy and DNA damaging therapeutic strategies in p53-positive tumors. HORMONAL REGULATION OF DNA REPAIR As outlined above, there are five basic categories of DNA damage repair [30C35]. To date, the majority of experimental evidence demonstrates that steroid hormones primarily regulate double-strand break (DSB) repair through non-homologous end joining (NHEJ) and homologous recombination (HR). Non-homologous end joining (NHEJ) NHEJ is the predominant pathway utilized to repair DSBs, which consists of a step-wise process of anchoring the broken ends of DNA to each other via the Ku70/Ku80/DNAPK protein complex, followed by end processing (if necessary), then ligation by the XRCC4/DNA ligase IV complex. To date, three independent studies have described the role of steroid hormones and their receptors in NHEJ, all of which implicate a positive regulation of NHEJ by NRs[44C46]. Both estrogens in BrCa and androgens in PCa were found to induce components of NHEJ. Each study emphasized a different component of NHEJ as being specifically responsible for steroid-induced DNA repair. In PCa model systems, DNAPK-cs (and . Moreover, tumors from PCa patients undergoing Adoprazine (SLV313) neo-adjuvant Adoprazine (SLV313) androgen deprivation therapy (removal of male hormones) harbored decreased Ku70 levels and increased levels of DNA damage as determined by H2AX foci (an indication of DNA double strand breaks) after prostatectomy . In BrCa model systems, it has been shown that estrogen signaling controls NHEJ via stimulation of NBS1 (Nibrin) expression through the concerted functions of c-Myc, p53, and the co-activators CBP (CREB binding protein) and SRC1 (Nuclear receptor coactivator 1) at the NBS1 gene locus . Combined, these studies indicate that abrogation of NHEJ, either directly or through removal of positive regulation by steroid hormone signaling, sensitized cells to genotoxic stress, indicating the biological importance of this crosstalk. In summary, androgens and estrogens positively regulate NHEJ, and therapeutic inhibition of NRs in PCa and BrCa results in irreparable DSBs. Homologous recombination (HR).