Role Of ARID1A Research Articles

Abstract IA26: Role of ARID1A in SWI/SNF chromatin remodeling and ovarian cancer.

Abstract ARID1A has emerged as the most frequently mutated chromatin remodeling protein in cancer and as a major tumor suppressor in endometriosis-associated cancers arising from the coelomic epithelium of the female reproductive tract. We have developed and characterized Arid1a conditional (floxed) and hypomorphic (valine-to-glycine substitution or V1068G) mutant mouse alleles. Mutant ARID1AV1068G is stably expressed and capable of assembling into a SWI/SNF complex with core catalytic properties, but nucleosome binding and promoter occupancy by ARID1A-containing SWI/SNF complexes (BAF-A) are reduced. Lowly penetrant hyperplastic outgrowths are observed within the oviducts of aged, hypomorphic Arid1aV1068G/+ females, but no tumors have been detected. Conversely, conditional inactivation of ARID1A in the ovarian surface epithelium (OSE) via intrabursal Adenovirus-CRE injection is not sufficient for tumor formation, but requires concurrent activation of the phosphoinositide 3-kinase catalytic subunit, PIK3CA. Remarkably, mouse ovarian tumor cells carrying the ARID1A-PIK3CA mutational pattern are genomically stable, chemoresistant and dependent on cell autonomous Interleukin 6 (IL-6) signaling pathway for continued growth and survival. We have further shown that concurrent ARID1A loss and PIK3CA activation leads to an epithelial-to-mesenchymal transformation phenotype in isolated OSE cells. Our data highlight potential gene dose-dependent differences in ARID1A tumor suppressor activity in coelomic epithelial cell derivatives and suggest that many key features of ovarian tumorigenesis are conferred by the ARID1A-PIK3CA mutational pattern. Hence, our efforts to parse the tumor suppressor roles of ARID1A-containing SWI/SNF complexes in endometriosis-associated gynecologic cancers should extend to the Müllerian-derived ductal epithelium and include activating phosphoinositide 3-kinase mutations. Citation Format: Ronald L. Chandler, Jesse Raab, Terry Magnuson. Role of ARID1A in SWI/SNF chromatin remodeling and ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr IA26.

Role of ARID1A for the clinicopathologic characteristics of clear cell carcinoma (CCC) of the ovary

Role of ARID1A for the clinicopathologic characteristics of clear cell carcinoma (CCC) of the ovary

Abstract 3564: ARID1A promotes endocrine resistance in ER+ breast cancer cells.

Abstract We recently identified the ARID1A gene as a new candidate tumor suppressor gene (TSG), mutated in the T47D cells, an ER+ breast cancer cell line. We have shown previously that re-expression of ARID1A in T47D cells inhibits both proliferation and anchorage-independent growth and also that nuclear expression of ARID1A is progressively decreased during the later stages of breast tumor progression. ARID1A encodes a member of the SWI/SNF family of proteins, which function to ‘remodel’ chromatin and thereby regulate gene expression programs. Most breast cancers express the estrogen receptor (ER), and are thus responsive to the mitogenic effects of the estrogen hormone as well as to the anti-proliferative effects of anti-estrogen therapies. To uncover the potential role of ARID1A in the regulation of estrogen signaling in ER+ breast cancer cells, we tested if re-expression of ARID1A may also affect estrogen-dependent growth. Surprisingly, we found that re-expression of ARID1A in T47D cells results in a decrease in the proliferative response of these cells to estrogen but also to a decrease in the viability of the cells in hormone-depleted conditions. Then, to further investigate if the loss of ARID1A may promote estrogen-independent growth, we silenced ARID1A expression by shRNA in MCF-7 cells that express moderate levels of ARID1A protein. We found that ARID1A-silencing increases the survival of MCF-7 cells in the absence of hormones. In addition, we also observed that phosphorylation of FAK and Src, whose activities have been suggested to be important in endocrine resistance, is highly increased in the absence of ARID1A. All together, these results suggest that loss of ARID1A can promote endocrine-resistance in ER-positive breast cancer cells. Citation Format: Catherine Chabot, Mark Basik. ARID1A promotes endocrine resistance in ER+ breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3564. doi:10.1158/1538-7445.AM2013-3564

Abstract A45: The tumor suppressor role of ARID1A in gynecologic cancer

Abstract ARID1A (BAF250A), a gene participating in the formation of a BRG1 SWI/SNF chromatin remodeling complex, has emerged as a potential tumor suppressor because of its frequent inactivating mutations in gynecological cancer (approximately 50% of ovarian clear cell and 30% of ovarian endometrioid carcinomas). The mutation is associated with loss of protein expression as assessed by immunohistochemistry. In this study, we analyzed ARID1A expression in a wide variety of carcinomas to determine the prevalence of ARID1A inactivation in carcinomas using immunohistochemical staining. Immunoreactivity was not detected in 36 (3.6%) of 995 tumors. Uterine low-grade endometrioid carcinomas showed a relatively high-frequency loss of ARID1A expression, as 15 (26%) of 58 cases were negative. Mutational analysis showed 10 (40%) of 25 uterine endometrioid carcinomas; none of 12 uterine serous carcinomas and none of 56 ovarian serous and mucinous carcinomas harbored somatic ARID1A mutations. These findings suggest that the molecular pathogenesis of low-grade uterine endometrioid carcinoma is similar to that of ovarian low-grade endometrioid and clear cell carcinoma, tumors that have previously been shown to have a high-frequency loss of expression and mutation of ARID1A. We further studied the functions of ARID1A and found that restoration of wild-type ARID1A expression in ovarian cancer cells harboring ARID1A mutations suppressed cellular proliferation and tumor growth in mice. Gene silencing of ARID1A in non-transformed epithelial cells enhanced cellular proliferation and tumorigenecity. Mutations in ARID1A and TP53 were mutually exclusive in tumor specimens, and knockdown of ARID1A affected multiple p53-regulated genes and pathways, including CDKN1A and SMAD3. The ARID1A/BRG1 complex bound to the promoters and enhanced transcriptional activity of CDKN1A and SMAD3 in a p53-dependent manner. We further showed that p21 mediated, at least in part, the tumor suppressive functions of ARID1A. These results provide new evidences that ARID1A functions as tissue-type-restricted tumor suppressor by directly modulating transcriptional activity of several p53-regulated genes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A45.

Frequent low expression of chromatin remodeling gene ARID1A in breast cancer and its clinical significance

Background: ARID1A gene encodes BAF250a which is a member of the ARID family of DNA-binding proteins and a subunit of human SWI/SNF-related complexes. Low expression of ARID1A has been correlated with specific tumor cell lines or specific pathological types of cancer tissue. The purpose of this study was to investigate the expression of ARID1A in invasive ductal breast carcinomas and to evaluate its clinicopathological characteristics and prognostic value. Methods: ARID1A mRNA expression was evaluated by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) in 40 pairs of fresh frozen breast cancer and normal breast samples. BAF250a expression was evaluated by immunohistochemistry in 112 paraffin-embedded surgical specimens of invasive breast cancers and 20 cases of matched normal breast tissues. We further analyzed the clinicopathological characteristics of ARID1A expression. Overall survival time was assessed by the Kaplan–Meier method and Cox regression model. Results: ARID1A mRNA expression was lower in breast cancer tissue than in corresponding normal tissue (P<0.001), and this decreased expression level was markedly associated with factors such as larger tumor size (P=0.038), higher stage (P=0.016), ER(−) (P=0.038), higher Ki-67 (P=0.025), P53 mutation (P=0.018) and ER(−)/PR(−)/Her-2(−) molecular subtype (P=0.044). With immunohistochemical staining, we showed that low BAF250a expression existed in 56% (63/112) of the breast cancers tissues. Low BAF250a expression was significantly associated with tumor stage (P=0.021), P53 (P=0.018), Ki-67 (P=0.031) and ER(−)/PR(−)/Her-2(−) molecular subtype (P=0.044). Low ARID1A expression was a predictor, not an independent, of overall survival. Conclusion: These data suggest that low ARID1A expression is frequent in breast cancers, and we need to investigate further the role of ARID1A and SWI/SNF complexes in breast tumorigenesis, especially in triple-negative breast cancer.

Imaging Nuclear Compaction With Partial Wave Spectroscopy for Detection of Early Carcinogenesis: Role of ARID1A

Imaging Nuclear Compaction With Partial Wave Spectroscopy for Detection of Early Carcinogenesis: Role of ARID1A