Abstract
The humanized monoclonal antibody-drug conjugate trastuzumab emtansine (T-DM1, Kadcyla) has been approved by the U.S. FDA to treat human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer. Despite its effectiveness in most patients, some are initially resistant or develop resistance. No biomarker of drug resistance to T-DM1 has been identified. Antibody-drug efficacy is associated with antibody internalization in the cell; therefore, cellular sensitivity of cells to the drug may be linked to cellular vesicle trafficking systems. Caveolin-1 is a 22 KD protein required for caveolae formation and endocytic membrane transport. In this study, the relationship between caveolin-1 expression and the chemosensitivity of HER-2-positive breast cancer cells to T-DM1 was investigated. Samples from 32 human breast cancer biopsy and normal tissue specimens were evaluated immunohistochemically for caveolin-1 expression. Caveolin-1 was shown to be expressed in 68% (22/32) of the breast cancer specimens. In addition, eight (72.7%, 8/11) HER-2 positive breast cancer specimens had a higher caveolin-1 expression than normal tissues. HER-2-positive BT-474 and SKBR-3 breast cancer cells that express low and moderate levels of caveolin-1, respectively, were treated with trastuzumab or its conjugate T-DM1. Cell viability and molecular localizations of caveolin-1, antibody and its conjugate were examined. Confocal microscopy showed that T-DM1 and caveolin-1 colocalized in SKBR-3 cells, which also were five times more sensitive to the conjugate in terms of cell survival than BT-474 cells, although T-DM1 also showed improved drug efficacy in BT-474 cells than trastuzumab treatment. Caveolin-1 expression in these lines was manipulated by transfection of GFP-tagged caveolin-1 or caveolin-1 siRNA. BT-474 cells overexpressing caveolin-1 were more sensitive to T-DM1 treatment than mock-transfected cells, whereas the siRNA-transfected SKBR-3 cells had decreased sensitivity to T-DM1 than mock-transfected SKBR-3 cells. The expression of caveolin-1 could mediate endocytosis and promote the internalization of T-DM1 into HER-2 positive cancer cells. Thus, caveolin-1 protein may be an effective predictor for determining the outcome of T-DM1 treatment in breast cancer patients.
Highlights
Human epidermal growth factor receptor 2 (HER-2) has been identified as oncoprotein in breast cancer
Despite the success of this therapeutic treatment, naked trastuzumab targeting of HER-2 expression in breast cancer is rarely curative by itself, and most of the effects of this drug are achieved in combination with chemotherapy [4,5,6,7]
In the study of Western blot protein evaluation, 8 (72.72%) of the 11 HER-2 positive breast cancer patients were found to have a high expression of caveolin-1 in tumor tissue than in the nontumor part of the patient (S3 Table)
Summary
Human epidermal growth factor receptor 2 (HER-2) has been identified as oncoprotein in breast cancer. The overexpression of HER-2 mRNA and protein occurs in 20–30% of invasive breast cancers and is a predictor of poor clinical outcome [1, 2]. In 2001, trastuzumab was approved by the Food and Drug Administration (FDA) in the USA for patients with advanced breast cancers that express HER-2 [3]. Despite the success of this therapeutic treatment, naked trastuzumab targeting of HER-2 expression in breast cancer is rarely curative by itself, and most of the effects of this drug are achieved in combination with chemotherapy [4,5,6,7]. There are adverse effects of combination therapy: 27% of patients treated concurrently with trastuzumab and anthracyclines, and 13% with trastuzumab and paclitaxed, had cardiotoxic side effects [8]
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