While the majority of published SWI/SNF studies have probed the consequence of subunit dysfunction for tumorigenesis, emerging evidence is indicative of specialized SWI/SNF subunit roles in tumor progression and therapeutic response. Global diminution of SWI/SNF activity (via loss of BRG1 and BRM) in non-small cell lung carcinoma correlates with poor overall survival, providing some of the strongest indication that overall SWI/SNF activity protects against tumor progression (15
). For BRG1, several lines of evidence support the notion that its loss can contribute to neoplastic development during later stages rather than in early steps. For example, Brg1+/-
mice develop mammary adenocarcinomas at a low penetrance (~12%) at approximately 12 months, despite showing no LOH in the tumors (33
). These results suggest that reduced BRG1 may allow a rare population of initiated cells to progress to neoplasia; otherwise, one would expect a more fulminant tumor phenotype in the Brg1+/-
mice considering the haploinsufficient phenotype of the mammary tumors. While many human tumor cell lines lack detectable BRG1 and BRM expression, BRG1-deficient mouse fibroblasts and embryonal carcinoma cells paradoxically fail to proliferate or grow poorly in culture (33
), and show dissolution of chromatin structure (Buorgo et al., in press). Apoptosis was observed in lung epithelia in vivo after deletion of both Brg1
). Taking these observations into account, it has been hypothesized that acquisition of cooperative genetic events during cellular transformation is needed to allow proliferation in the absence of BRG1 and BRM. Further supporting the notion that BRG1 loss can contribute to tumor progression, high frequency of LOH (75%) in NSCLC was shown to occur in late stage and metastatic samples but not early stage disease (25
). Most dramatically, loss of BRG1 expression in acute lymphoblastic leukemia (ALL) strongly correlated with therapeutic resistance to prednisolone, and subsequent in vitro modeling showed that BRG1 knockdown was sufficient to achieve therapy resistance (85
). Some parallels with SNF5 are noted, as downregulation of this subunit has also been linked to steroid resistance in ALL (85
). While the resultant tumor phenotypes are distinct in different tissues, these data strongly support a role for BRG1 loss in tumor progression.
Unique profiles of loss and tumor progression were also observed with the BRM ATPase. Exemplifying the distinction between subunits, BRM but not BRG1 loss is a hallmark of the “poor” (poorly differentiated) form of gastric cancer, which is associated with unfavorable prognosis (41
). Mouse models also hint toward a link between BRM loss and therapeutic response in prostate cancer, as Brm
deletion resulted in modest androgen-independent cellular proliferation of selected prostatic epithelia in vivo
). Since androgen deprivation is the first line of therapeutic intervention for patients with disseminated disease, and the ability of tumors to circumvent androgen ablation (referred to as the transition to castration-resistant prostate cancer) represents an incurable phase, investigation of BRM loss on this event warrants further investigation. BRM status and response to hormonal-based therapies may also be of interest in breast cancer, since BRM is critical for the in vitro
response to tamoxifen (88
). BRM may also modify the response to genotoxic stress, as BRM loss alters DNA damage checkpoints in vitro
), and loss of BRM occurs as an early response to ionizing radiation in esophageal squamous cell carcinomas. Most significantly, BRM loss was identified as an indicator of poor prognosis in non-small cell lung cancer. Patients with lung adenocarcinomas or squamous cell carcinomas incurred a 5-year survival rate of 72% if positive for BRM and BRG1, but only 32.3% if deficient in BRM or BRG1. Intriguingly, altered subcellular (membrane) localization of BRM was associated with a 16.7% survival rate (15
). These findings are striking, as of 12 chromatin remodeling proteins examined, only BRM showed prognostic significance. Based on these findings, it is clear that the mechanisms by which BRM alters therapeutic response and alters the course of disease should be determined.
Despite the evidence linking ATPase alterations to tumor development and progression, few studies have addressed the impact of SWI/SNF function on invasion and metastasis in the clinic, and the GEMM provided little evidence linking loss of SWI/SNF to a metastatic phenotype. Therefore, only in vitro
studies have provided clues regarding a potential role for alterations in complex subunit expression in metastasis. In vitro
restoration of BRM in BRM-deficient lung cancer cells resulted in reduced soft agar and invasion capabilities(38
), thus giving some indication that BRM may influence lethal tumor phenotypes. Additionally, BRG1 and/or BRM can regulate the expression of proteins associated with metastatic spread in a variety of human cancers, including CD44, CDH1 and actin filament organization (89
). While these findings are provocative, further studies are needed using primary human tumor material and GEMM to definitively address the role of the SWI/SNF ATPases in the metastatic phenotype.
Within the core and accessory subunit categories, scant evidence exists to determine whether these subunits contribute to tumor progression. A recent report showed that loss of SNF5 protein expression occurs in renal medullary carcinoma, a rare malignancy associated with young adults, or in children with sickle cell trait or disease (92
). In the case of MRT, it could be argued that SNF5 loss may play a role in tumor progression because no other report of additional genetic defects has appeared in the literature (93
). However, most studies have examined only primary tumors and MRT cell lines and may have missed secondary genetic events. Progressive disease, metastases, and recurrences should be examined and compared with primary disease so that later events can be examined. For the accessory proteins, the individual subunits show widely varied influences on progression and treatment. Interestingly, BAF57 was recently identified in a high-throughput shRNA library screen as one of 5 genes (along with SNF5) required for the response of CML to imatinib(94
). The same study identified BAF250a as required for the response to Fas ligand, thus further implicating the SWI/SNF subunits as putative effectors of chemotherapy. BAF45a, although known for a role in neural progenitor cells(7
), was recently identified in a gene signature indicating favorable prognosis in colorectal cancer.
Based on these findings, it can be concluded that the SWI/SNF ATPases appear to have significant, disparate roles in protecting against tumor progression. The requirement of individual cooperating subunits for these functions will be of the utmost importance to discern.