Abstract 722: Caveolin-1-dependent endocytosis enhanced chemosensitivity of TDM-1 in HER-2-positive breast cancer cells

Abstract

Abstract Trastuzumab emtansine (TDM-1, kadcyla) is the antibody drug conjugate (ADC) was approved to treat HER-2 positive metastatic breast cancer. Although its effectiveness, however, the biomarker of drug resistance of TDM-1 has not been identified. The efficacy of ADC is restricted to the antibody internalization in the cell; therefore, the drug sensitivity may be associated with cellular vesicle trafficking system. Caveolin-1, which is the 21 KD membrane protein that is required for caveolae structure formation and membrane endocytic transport. In this study, the relationship of caveolin-1 expression and the chemosensitivity of TDM-1 in HER-2 positive breast cancer cells was investigated. Immunohistochemical staining of 32 specimens of breast cancer patients were evaluated for caveolin-1 expression. For in vitro study, BT-474 and SKBR-3 breast cancer cells which represent different caveolin-1 expression were treated with trastuzumab or T-DM1. Cell viability and molecular localization were examined. Cellular caveolin-1 expression was also manipulated by transfection of GFP tagged caveolin-1 or caveolin-1 shRNA plasmid, cell viability was then determined after drug treatment. In the results, Immunohistochemical study showed 68% (22/32) overexpression of Caveolin-1 in breast cancerous specimens. And eight cases with high expression of Caveolin-1 were found in HER-2 positive breast cancerous patients (72.1%, 8/11). In cell biology study, T-DM1 was found colocalized with caveolin-1 by confocal microscopy. SKBR-3 which represents higher caveolin-1 expression than BT-474 was more sensitive to T-DM1 treatment. After molecular transfection, BT-474 cells with overexpression of caveolin-1 increased chemosensitivity in the treatment of TDM-1, instead, SKBR-3 cells transfected with caveolin-1 shRNA decreased T-DM1 sensitivity. Expression of caveolin-1 could mediate endocytosis and promoting the internalization of TDM-1 into HER-2 positive cancer cells. Thereafter, caveolin-1 may be an effective predictor for TDM-1 treatment in the future. Citation Format: Yuan-Chiang Chung, Wan-Chen Wei, King-Jen Chang, Wei-Ting Chao. Caveolin-1-dependent endocytosis enhanced chemosensitivity of TDM-1 in HER-2-positive breast cancer cells. [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 722. doi:10.1158/1538-7445.AM2015-722