Abstract A20: Decreased nuclear expression of the FRY protein identifies a subset of breast cancers with poor clinical outcomes

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Abstract The goal of the present study was to determine if decreased nuclear expression of the human FRY protein can serve as a biomaker of breast cancer progression and outcomes. We previously identified the rat Fry gene as a putative mammary carcinoma susceptibility (Mcs) gene. We further demonstrated that FRY expression was decreased in several human breast cancer cell lines. Moreover, ectopic expression of wildtype Fry suppressed tumorigenicity of the triple negative MDA-MD-231 breast cancer cells in vitro and in vivo by promoting epithelial cell differentiation. To evaluate the contribution of altered FRY expression to the clinical progression of human breast cancer, we first compared FRY mRNA expression in >4,800 clinically annotated human breast cancers using DNA microarray data from 19 distinct cohorts available from the Oncomine 3.0 Cancer Profiling Database. The analysis indicated that decreased FRY mRNA was significantly correlated with poorly differentiated tumor histopathology, increased Elston tumor grade, and triple negative status (loss of estrogen, progesterone and Her2 receptors). Using commercially available breast cancer tissue microarrays, we used semi-quantitative immunohistochemistry and quantitative image analysis to compare FRY protein expression in normal mammary tissue and tumors. The results indicated that loss of FRY expression was a frequent event during progression of mammary carcinomas. We therefore analyzed >1200 clinically annotated breast cancers represented on tissue microarrays from commercial suppliers and the National Cancer Institute (NCI) Cancer Diagnosis Program, including the Breast Cancer Diagnosis and Progression panels. FRY protein expression was evaluated by immunohistochemical staining and was graded on a scale of 0 to 4 (0, +, ++, +++, ++++). The analysis indicated that decreased nuclear expression of the FRY protein was significantly correlated with poorly differentiated histopathologies, increasing Elston grade and loss of the estrogen receptor. Tumors with decreased FRY expression were also more likely to metastasize and were associated with decreased tumor-free survival. These findings indicated that loss of nuclear FRY expression identifies a subset of breast cancer with poor clinical outcomes, suggesting that FRY may serve as an early biomarker for breast cancer progression and prognosis. Citation Format: Helmut Zarbl, Jessica C. Graham, Norio Takizawa, Mingzhu Fang, Zhihong Gong, Brian Estrella, Xuefeng Ren. Decreased nuclear expression of the FRY protein identifies a subset of breast cancers with poor clinical outcomes. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A20.