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.
Although HER2 overexpression and Her2 amplification have been noted in breast and a variety of human cancers, we report here for the first time the impact of polysomy-17 on HER2 status and the correlations between HER2 status and other prognostic factors in patients with epithelial ovarian cancers (EOC).We analyzed HER2, estrogen receptor (ER), progesterone receptor (PR), p53, and Ki-67 protein overexpressions by immunohistochemistry (IHC) and determined Her2 gene amplification by fluorescence in situ hybridization (FISH) in 27 tissue microarray samples from EOC patients.We achieved 100% positive concordance (3/3) and 100% negative concordance (19/19) between HER2 testing by IHC and FISH. Both the total Her2 gene copies and FISH scores increased significantly in a stepwise order through the negative, equivocal, and positive HER2 IHC result categories in all 27 cases (P=0.001, P=0.001), and still increased significantly in 18 nonpolysomy-17 cases (P=0.007 and 0.013) after the exclusion of 9 polysomy-17 cases. HER2 protein expression is inversely correlated with both ER (P=0.002) and PR expressions (P=0.046). Her2 gene amplification is inversely correlated with ER expression (P=0.007) but not with PR expression (P=0.106).This study showed extremely high positive and negative concordances between Her2 FISH and HER2 IHC assays. Polysomy-17 is insufficient for causing a significant impact on the relationship between HER2 testing by IHC and FISH in EOC. ER and PR expressions were inversely correlated with HER2 protein expression. In addition, ER but not PR expression is inversely correlated with Her2 gene amplification.
1. Unk I, Hajdu I, Fatyol K et al. Human HLTF functions as a ubiquitin ligase for proliferating cell nuclear antigen polyubiquitination. Proc. Natl Acad. Sci. USA 2008; 105; 3768-3773. 2. Blastyak A, Hajdu I, Unk I, Haracska L. Role of double-stranded DNA translocase activity of human HLTF in replication of damaged DNA. Mol. Cell. Biol. 2010; 30; 684-693. 3. Debauve G, Capouillez A, Belayew A, Saussez S. The helicase-like transcription factor and its implication in cancer progression. Cell. Mol. Life Sci. 2008; 65; 591-604. 4. Capouillez A, Decaestecker C, Filleul O et al. Helicase-like transcription factor exhibits increased expression and altered intracellular distribution during tumor progression in hypopharyngeal and laryngeal squamous cell carcinomas. Virchows Arch. 2008; 453; 491-499. 5. Capouillez A, Debauve G, Decaestecker C et al. The helicase-like transcription factor is a strong predictor of recurrence in hypopharyngeal but not in laryngeal squamous cell carcinomas.
I read with great interest the article by Cooperberg and coworkers 1 studying survival rates in differently treated men with early prostate cancer. In this study, patients who underwent radical prostatectomy had a substantially decreased disease-specific mortality, particularly in the higher-risk groups, compared with those who were selected for radiation therapy or conservative management. 1 Unlike Cooperberg et al., I do not consider it unlikely that unmeasured confounding, at least in part, accounted for the observed differences. It is conceivable that patients with a particularly adverse profile within the same risk category might have preferably been referred to external-beam radiotherapy, thus putting this treatment modality at a disadvantage. It is questionable whether this phenomenon is adequately covered by conventional prognostic factors because subjective clinical judgment is included. Selection in favor of surgery is a problem when different treatments for early prostate cancer are compared. 2,3 Even careful risk adjustment will hardly be able to eliminate this effect completely. 3,4 Otherwise, it would be difficult to justify randomized trials comparing radical prostatectomy and external-beam radiotherapy in this setting that the authors rightly called for. 1
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