Abstract 2704: Tetraspanin CD151 drives mammary tumor onset and metastasis by coordinating integrin-dependent cell adhesion, motility, survival and signaling

• Published in: Cancer research (Chicago, Ill.) Vol. 72; no. 8_Supplement; p. 2704
• Main Authors: Deng, Xinyu, Hoff, John, Novak, Marian, Kaetzel, David, Hemler, Martin E., Yang, Xiuwei H.
• Format: Journal Article
• Language: English
• Published: 15.04.2012
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2012-2704

Abstract The ErbB2+ subtype of human breast tumors remains a significant threat to women's health, as they are highly prone to recurrence or metastasis, and development of drug resistance. Here we report that CD151, a member of the tetraspanin family and a close partner of the laminin-binding (LB) integrins (≥3α1 and α6β4), contributes to the onset and malignancy of ErbB2-induced mammary tumors. By crossing gene-targeted mice onto a clinically-relevant MMTV-ErbB2 transgenic model, we demonstrated that deletion of CD151 significantly impaired the onset and metastasis of mammary tumors in mice. Our subsequent analyses of cell lines derived from mouse primary tumors showed that loss of CD151 decreased integrin-mediated cell-ECM adhesion and cell-cell contacts. Also, for ErbB2-overexpressing MCF-10A cells cultured in 2D or 3D, ablation of CD151 markedly reduced tumor cell motility, invasion and survival. However, only MAPK and FAK kinases among an array of signaling molecules downstream of integrins and ErbB receptors, exhibited a decreased activation in response to CD151 disruption. Importantly, there were corresponding changes in the activation and signaling of α6β4 integrin, as reflected by decreased phosphorylation of multiple serine residues at its cytoplasmic domain. Also, the cross-talk between integrins and ErbB receptors was strongly inhibited. Meanwhile, our analyses of clinical dataset revealed a strong correlation between CD151 gene expression and patients’ metastasis-free survival. Taken together, our results demonstrate that tetraspanin CD151 drives ErbB2-induced mammary tumorigenesis by coordinating the function and signaling of LB integrins. This newly-identified crucial role of CD151 offers a strong therapeutic potential for the treatment of breast cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2704. doi:1538-7445.AM2012-2704