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Targeting Steroid Receptor Coactivators in Cancer David M Published OnlineFirst September 21, 2016; DOI: 10.1158/1078-0432.CCR-15-1958 Molecular Pathways Clinical Cancer Research Molecular Pathways: Targeting Steroid Receptor Coactivators in Cancer David M. Lonard and Bert W. O'Malley Abstract Coactivators represent a large class of proteins that partner made to develop SRC-targeting agents, such as the SI-2 inhib- with nuclear receptors and other transcription factors to regu- itor and the novel SRC stimulator, MCB-613, that are able to late gene expression. Given their pleiotropic roles in the control block cancer growth in cell culture and animal model systems. of transcription, coactivators have been implicated in a broad Here, we will discuss the mechanisms through which coacti- range of human disease states, including cancer. This is best vators drive cancer progression and how targeting coactivators typified by the three members of the steroid receptor coacti- represent a novel conceptual approach to combat tumor growth vator (SRC) family, each of which integrates steroid hormone that is distinct from the use of other targeted therapeutic agents. signaling and growth factor pathways to drive oncogenic gene We also will describe efforts to develop next-generation SRC expression programs in breast, endometrial, ovarian, prostate, inhibitors and stimulators that can be taken into the clinic for and other cancers. Because of this, coactivators represent emerg- the treatment of recurrent, drug-resistant cancers. Clin Cancer Res; ing targets for cancer therapeutics, and efforts are now being 22(22); 1–5. Ó2016 AACR. Background SRCs in addition to histones, altering SRC activity and protein stability (6). In addition to SRCs, these SRC-associated co- The nuclear receptors (NR) gene superfamily consists of ligand- coactivators provide an entree for therapeutic interventions activated transcription factors that respond to steroid and other with small-molecule inhibitors (SMI), such as the p300 HAT lipophilic hormones, or that in some cases are "orphan" receptors inhibitor C646 (7). for which no ligand exists or has been identified to date (1). NRs regulate a diverse array of physiologic processes and, as a conse- quence, are often coopted by cancer cells to drive tumor growth. SRCs in breast cancer However, a large body of research has reinforced the notion that Because of their strong connection with NRs, SRC proteins NRs cannot drive transcription by themselves and rely on coacti- have been recognized as key oncoproteins in hormone-depen- vators to act as key intermediaries needed to modify and interpret dent cancers. For instance, elevated SRC expression and activity the epigenome and signaling functions as essential enablers for is a driving force in the initiation and progression of ERa- NR-mediated transcription. positive breast cancers. The SRC-3 gene is amplified in 5% to At this time, more than 400 coactivators have been reported in 10% of breast cancers (8, 9), and the SRC-3 mRNA or protein the literature (2). The first identified coactivator, steroid receptor has been found to be overexpressed by approximately 60% in coactivator 1 (NCOA1/SRC-1), was characterized as a protein that different breast cancer patient cohorts (8, 10, 11). SRC-3 over- can stimulate the transcriptional activities of the progesterone expression was found to be associated with more aggressive receptor, the estrogen receptor a (ESR1/ERa), and other NRs (3). breast cancers (9, 12) and poor survival rates (13). Consistent Two other members of the SRC family, SRC-2 (NCOA2/TIF2/ with this, clinical data from breast cancer patients indicate that GRIP1) and SRC-3 (NCOA3/AIB1/RAC3/ACTR/pCIP), were sub- high SRC-3 expression is associated with decreased disease-free sequently identified (4), and SRCs have been substantiated as the survival (14). In genetically engineered MMTV-v-ras and primary platform coactivators that serve as scaffolds for building a MMTV-Erbb2 mouse models, loss of SRC-3 reduces breast multi-protein coactivator protein complex containing co-coacti- tumor incidence and delays tumor growth and development vator chromatin-modifying enzymes, including CREB-binding (15, 16). In both models, insulin-like growth factor 1 (IGF1) protein (CREBBP/CBP), p300 (EP300), coactivator-associated and ERBB2 signaling pathways are impaired in the absence of arginine methyltransferase 1 (CARM1), and other proteins (5). SRC-3, implicating that kinase signaling cascades independent In many cases, these co-coactivators posttranslationally modify of ERa are also involved in coactivator-dependent breast cancer tumor progression. Expanding on this idea that SRCs can drive multiple cancer growth signaling systems, SRC-3 has been Department of Molecular and Cellular Biology, Baylor College of shown to coactivate other transcription factors, such as the Ets Medicine, Houston, Texas. transcription factor polyoma enhancer activator 3 (PEA3), Corresponding Author: Bert W. O'Malley, Department of Molecular and Cellular leading to increased expression of matrix metalloproteinase Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. 2 (MMP2) and MMP9, leading to metastasis (17). Phone: 713-798-6205; Fax: 713-798-5599; E-mail: [email protected] The multifunctional role for SRC-3 as a broad integrator of doi: 10.1158/1078-0432.CCR-15-1958 additional cancer cell growth programs is further reinforced by the Ó2016 American Association for Cancer Research. finding that a splice variant of SRC-3 (SRC-3D4) functions as a www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst September 21, 2016; DOI: 10.1158/1078-0432.CCR-15-1958 Lonard and O'Malley AB Escape pathways not Steroid receptor coactivator (SRC)- inhibited by current targeted targeting agents simultaneously block therapeutic agents multiple cancer growth pathways Figure 1. SRC-based drugs are predicted to block cancer cell resistance to Targeted therapies SRC SMI Buparlisib chemotherapy. SRCs bind to DNA- bound transcription factors (TF) and CBP/p300 CARM1 SERMs, SERDs subsequently recruit co-coactivators, Herceptin CBP/p300 CARM1 lapatinib SRCs such as p300/CBP and CARM1, forming SRCs a coactivator complex that drives TF TF TF TF transcription. A, chemotherapeutic agents designed to target ERa,suchas selective ER modulators (SERMS) and degraders (SERD), HER2 (Herceptin and lapatinib), or PI3K (buparlisib) cannot block coactivator stimulation of HER2/ PI3K/ ERα or ERα HER2/ PI3K/ other growth-promoting pathways ERα E2F1 NF-κB E2F1 NF-κB neu AKT mutants neu AKT driven through E2F1 or NF-kBin SRC-3–overexpressing cancer cells. B, in contrast, an SRC-targeting SMI is predicted to simultaneously inhibit constitutively active ERa mutants that arise in endocrine therapy–resistant Cancer cell Cancer cell breast cancers and different growth pathways that are concomitantly activated when SRCs are overexpressed, blocking their ability to Cancer cell evades growth Cancer cell cannot evade SRC access alternative growth pathways inhibition by exploiting SMI that broadly disrupts that become active in endocrine alternative growth pathways multiple growth pathways therapy or chemotherapy-resistant cancer cells. © 2016 American Association for Cancer Research bridging adaptor between the EGFR and focal adhesion kinase target the transcriptional function of these gain-of-function (FAK), potentiating cancer cell migration and invasion in a non- mutant ERa proteins (Fig. 1). genomic manner (18). SRCs in prostate, endometrial, and ovarian cancer Role of SRCs in endocrine therapy–resistant breast cancers A comprehensive sequencing analysis of human prostate SRC-3 has been implicated in clinical resistance to tamoxifen tumors found that 8% of primary and 37% of metastatic tumors and aromatase inhibitors, and this has been traditionally attrib- either have amplifications of the SRC-2 gene or overexpress its uted to the role that SRC-3 has in stimulating growth factor mRNA (24). Primary prostate tumors with SRC-2 gain of function signaling pathways, circumventing the inhibition of ERa in breast have elevated androgen receptor (AR) signaling, consistent with cancer cells (19, 20), consistent with the pleiotropic actions that the known role of SRC-2 as an AR coactivator. These findings are we have described for SRC-3 above. Recent studies that have in agreement with earlier studies that showed a correlation sought to uncover genomic alterations that underlie endocrine between SRC-2 expression and high tumor grade and poor therapy resistance have provided additional layer of detail point- survival (25–27). Interestingly, SRC-2 has been shown to be a ing to a role for SRC-3 in recurrent breast cancer. Sequencing of key regulator of energy homeostasis (28–31), and this fact has tumors from breast cancer patients that have acquired resistance been linked to its role as a regulator of prostate cancer metabolic to aromatase inhibitors has revealed the presence of recurrent programming. Specifically, SRC-2 drives glutamine-dependent mutations in the ligand-binding domain of the ERa gene, result- and sterol-regulatory element–binding protein 1 (SREBP1)– ing in activation of the receptor in the absence of estrogens (21). mediated de novo lipogenesis that enhances prostate cancer cell These mutant receptors also are refractory to the pure antiestrogen survival and metastasis (32). SRC-3 and SRC-1 have also been fulvestrant, and considerable effort has been directed toward the reported
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