Abstract 4020: Identifying the role of CRYBB2 in breast cancer tumor-tumor and tumor-stromal interactions

Despite the many advances in detection and diagnosis, breast cancer (BrCa) is still the second leading cause of cancer deaths in women of the US. The disproportionate rates of mortality and morbidity of BrCa in African American (AA) woman remains an alarming statistic. While studies have intensified investigating genetic profiles and subtypes (luminal A, B, Her-2 and basal-like) contributing to this disease, the mechanisms associated with poor prognosis and survival are still unclear. More recent studies show the tissue microenvironment is also a major contributor to differences in tumor biology and possibly BrCa health disparities. Studies have identified two genes, CRYBB2 and PSPH, differentially expressed in AA and Caucasian American women in colorectal, prostate and breast cancers. In particular, increased CRYBB2 expression has been associated with poor prognosis, race, and BrCa subtype. While the genetic profile of CRYBB2 provides insight into differentially regulated biological markers, the mechanism and role of CRYBB2 in the tumor and tumor-microenvironment interactions has not been studied. We hypothesized that protein expression of CRYBB2 is associated with subtype-specific BrCa progression and contributes to changes in the metastatic potential of BrCa. The goal of this study was to: (1) identify CRYBB2 protein localization and expression in luminal and basal-like BrCa cells and stromal cells, (2) determine signaling pathways regulating CRYBB2 protein expression and, (3) investigate the biological functions of CRYBB2 including proliferation and migration. Our in vitro studies show increased CRYBB2 protein expression during BrCa progression and altered CRYBB2 protein levels in stromal cells. CRYBB2 protein localization was primarily cytoplasmic in basal-like BrCa and stromal cells, but displayed distinct membrane localization in luminal BrCa cells. Moreover, we show hepatocyte growth factor (HGF)-regulation of CRYBB2 protein levels in luminal BrCa cells, and that the PI3K/AKT signaling pathway is responsible, in part, for the observed regulation. Furthermore, we show that stromal overexpression of CRYBB2 stimulates altered secretion of growth factors and cytokines that modify the migratory and proliferative capacity of luminal BrCa cells. These data suggest that regulation of CRYBB2 expression in tumors is also a consequence of changes initiated by the stromal microenvironment. This study is the first to report cell type-specific CRYBB2 protein localization as well as stromal-regulation of CRYBB2 levels and subsequent functional properties in BrCa cells, an important step in advancing our understanding of the mechanisms regulating BrCa progression, tumor- and stromal microenvironmental interactions, and cancer health disparities. Citation Format: Lynnelle Thorpe, Jasmine Young, Melissa A. Troester, Jodie M. Fleming. Identifying the role of CRYBB2 in breast cancer tumor-tumor and tumor-stromal interactions. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4020. doi:10.1158/1538-7445.AM2015-4020