J Cancer 2017; 8(1):1-8. doi:10.7150/jca.16602
Downregulation of ARID1A, a component of the SWI/SNF chromatin remodeling complex, in breast cancer
1. Department of Surgical Oncology, Gifu University, Gifu University Graduate School of Medicine, Gifu, Japan;
2. Department of Surgery, Kizawa Memorial Hospital, Minokamo, Japan;
3. Department of Pathology and Translational Research, Gifu University Graduate School of Medicine, Gifu, Japan;
4. Department of Breast and Molecular Oncology, Gifu University Graduate School of Medicine, Gifu, Japan.
Takao C, Morikawa A, Ohkubo H, Kito Y, Saigo C, Sakuratani T, Futamura M, Takeuchi T, Yoshida K. Downregulation of ARID1A, a component of the SWI/SNF chromatin remodeling complex, in breast cancer. J Cancer 2017; 8(1):1-8. doi:10.7150/jca.16602. Available from http://www.jcancer.org/v08p0001.htm
Recent studies unraveled that AT-rich interactive domain-containing protein 1A (ARID1A), a subunit of the mammary SWI/SNF chromatin remodeling complex, acts as a tumor suppressor in various cancers. In this study, we first evaluated ARID1A expression by immunohistochemistry in invasive breast cancer tissue specimens and assessed the correlation with the prognosis of patients with breast cancer. Non-tumorous mammary duct epithelial cells exhibited strong nuclear ARID1A staining, whereas different degrees of loss in ARID1A immunoreactivity were observed in many invasive breast cancer cells. We scored ARID1A immunoreactivity based on the sum of the percentage score in invasive cancer cells (on a scale of 0 to 5) and the intensity score (on a scale of 0 to 3), for a possible total score of 0 to 8. Interestingly, partial loss of ARID1A expression, score 2 to 3, was significantly correlated with poor disease free survival of the patients. Subsequently, we performed siRNA-mediated ARID1A knockdown in cultured breast cancer cells followed by comprehensive gene profiling and quantitative RT-PCR. Interestingly, many genes were downregulated by partial loss of ARID1A, whereas RAB11FIP1 gene expression was significantly upregulated by partial loss of ARID1A expression in breast cancer cells. In contrast, a more than 50% reduction in ARID1A mRNA decreased RAB11FIP1gene expression. Immunoblotting also demonstrated that partial downregulation of ARID1A mRNA at approximately 20% reduction significantly increased the expression of RAB11FIP1 protein in MCF-7 cells, whereas, over 50% reduction of ARID1A mRNA resulted in reduction of RAB11FIP1 protein in cultured breast cancer cells. Recent studies reveal that RAB11FIP1 overexpression leads to breast cancer progression. Altogether, the present findings indicated that partial loss of ARID1A expression is linked to unfavorable outcome for patients with breast cancer, possibly due to increased RAB11FIP1 expression.
Keywords: ARID1A, breast cancer, prognosis, chromatin remodeling complex, RAB11FIP1.