Abstract
Abstract Breast cancer is expected to be the most frequently diagnosed form of cancer and the second leading cause of cancer deaths among women in 2012. The primary objective of the present study was to provide insights into the molecular mechanisms underlying the aggressive growth of triple-negative and basal-like breast cancers. In this study, we use the Tamoxifen-selected, MCF-7 derivative, TMX2-28 breast cancer cell line. TMX2-28 cells are triple-negative, have acquired a mixed basal/luminal cytokeratin profile, suggestive of a more basal-like phenotype, and are highly proliferative. We also examined thirty frozen breast carcinoma samples for mRNA, and 188 breast tumors and 50 benign reduction mammoplasty samples (formalin-fixed paraffin embedded) for protein expression. S-phase kinase-associated protein 2 (SKP2) plays an important role in cell cycle regulation by targeting p27 for degradation. The cyclin-dependent kinase (CDK) inhibitor p27 regulates G1/S transition by binding cyclin/CDK complexes and abrogating its activity. By targeting p27 for degradation, SKP2 frees the complexes needed to progress into the S phase of the cell cycle. Evaluation of SKP2 expression in TMX2-28 revealed significantly higher levels than in other breast cancer cell lines. Despite the high levels of SKP2 expression, p27 protein was not reduced. However, levels of the serine-10 phosphorylated form of p27 (pSer10p27), which has been associated with increased proliferation rates, was found to be upregulated. Furthermore, suppression of SKP2 completely eliminated pSer10p27 expression and slowed cell cycle progression confirming the role of SKP2 in the aggressive growth of TMX2-28 cells. Assessment of mRNA from 30 frozen human breast cancers demonstrated that SKP2 is more highly expressed in ERα-negative and basal-like breast cancers. Immunohistochemical analysis confirmed that SKP2 is more highly expressed in ERα-negative breast cancers and for the first time demonstrated that triple-negative breast cancers are more likely to overexpress SKP2 than are non-triple negative, but still ERα-negative tumors. We did not observe an inverse relationship between SKP2 and p27 expression, however a significant positive relationship was discovered between SKP2 and pSer10p27. Furthermore, high levels of SKP2 and pSer10p27 were observed significantly more often in ERα-negative and triple-negative than in ERα-positive breast cancers. The relationship between SKP2 and pSer10p27 is a better indicator of increased tumor proliferation in triple-negative breast cancers based on these results and those of our cell culture model. Inhibiting SKP2 in tumors expressing high levels of both SKP2 and pSer10p27 may be a valid therapeutic approach. Citation Format: Katerina D. Fagan-Solis, Joseph M. Gogzit, Brook A. Bentley, Sharon M. Marconi, Christopher N. Otis, Douglas L. Anderton, Sallie Smith Schneider, Brian T. Pentecost, Kathleen F. Arcaro. SKP2 overexpression is associated with increased serine-10 phosphorylation of p27 (pSer10p27) in triple-negative breast cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 563. doi:10.1158/1538-7445.AM2013-563
Published Version
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