CD151 Accelerates Breast Cancer by Regulating α6 Integrin Function, Signaling, and Molecular Organization

Abstract

CD151, a master regulator of laminin-binding integrins (A 6 B 4 , A 6 B 1 , and A 3 B 1 ), assembles these integrins into complexes called tetraspanin-enriched microdomains. CD151 protein expression is elevated in 31% of human breast cancers and is even more elevated in high-grade (40%) and estrogen receptor-negative (45%) subtypes. The latter includes triplenegative (estrogen receptor, progesterone receptor, and HER2 negative) basal-like tumors. CD151 ablation markedly reduced basal-like mammary cell migration, invasion, spreading, and signaling (through FAK, Rac1, and lck) while disrupting epidermal growth factor receptor (EGFR)-A 6 integrin collaboration. Underlying these defects, CD151 ablation redistributed A 6 B 4 integrins subcellularly and severed molecular links between integrins and tetraspanin-enriched microdomains. In a prototypical basal-like mammary tumor line, CD151 ablation notably delayed tumor progression in ectopic and orthotopic xenograft models. These results (a) establish that CD151-A 6 integrin complexes play a functional role in basallike mammary tumor progression; (b) emphasize that A 6 integrins function via CD151 linkage in the context of tetraspanin-enriched microdomains; and (c) point to potential relevance of CD151 as a high-priority therapeutic target, with relative selectivity (compared with laminin-binding integrins) for pathologic rather than normal physiology. [Cancer Res 2008;68(9):3204-13]

CD151 in cancer progression and metastasis: a complex scenario

“…Several other reports seem to be in agreement that CD151 has no effect on integrin conformation/activation. 34,41,42 As demonstrated by Yamada and co-workers in A549 cells, a CD151 was involved in modulation of two independent aspects of integrin a3b1 functions, namely, potentiation of a3b1-mediated cell adhesion and promotion of a3b1-stimulated signalling events involving tyrosine phosphorylation. Knockdown of CD151 resulted in formation of aberrant membrane protrusions and reduction in phosphorylation of focal adhesion kinase (FAK), Src, p130Cas and paxillin in cells grown on laminin-511.…”

“…31 CD151 is clustered at the cell membrane in specialized multimeric aggregates, ie, tetraspanin-enriched microdomains (TEMs or 'tetraspanin web'). It is postulated that at the molecular level, this tetraspanin is a lateral organizer and modulator of activities of transmembrane proteins such as adhesion molecules, ie, laminin-binding integrins, 19,32 growth factor receptors (HGFR, EGFR and TGFbR) 26,33,34 and proteases. 24,35 The functional association with numerous proteins indispensable for tumour progression implies a regulatory role for CD151 at different stages of disease development.…”

“…12 Signalling CD151 is a master regulator of signalling mediated by laminin-binding integrins. It acts directly on signalling, that is, on downstream effectors crucial for motility of many types of cancer cells, for example, FAK, 34,52 Src, Erk1/2, 53 p38, 26 Rac1 and Ick 34 in BCa cell lines; FAK, Src, p130Cas and paxillin in human lung adenocarcinoma cell line A549; 43 FAK, Src, p38 and JNK kinases in human melanoma cell lines. 21,24 In the MDA-MB-231 mammary cancer cell line, the CD151-a3b1 integrin complex was shown to participate in invasive migration in 3D environment.…”

“…26 In BCa cells (MDA-MB-231), CD151 ablation was proven to disrupt EGFR-a6 integrin interaction subsequently affecting cell migration, invasion and spreading in response to EGF. 34 Existing studies describing CD151 involvement in communication between tumour and its microenvironment have primarily focussed on an impact of its presence on the membrane of cancer cells on cellular response to the stimuli generated by the stroma. As CD151 is ubiquitously expressed, its contribution to the reverse feedback, that is, the interactions between CD151-expressing stromal cells and the tumour, or even more systemic response involving the immune system, are highly probable.…”

“…Clinically, high levels of CD151 are correlated with poor prognosis in a variety of tumours including epithelial malignancies such as carcinomas of the lung, 68 breast (invasive ductal carcinoma), 34,53,69 colon, 70 pancreas, 71 kidney, 10 prostate (PCa), 72 liver 73,74 and oesophagus (SCC), 75 as well as glioblastoma. 76 As in most cancers an elevated level of CD151 expression is associated positively with a high tumour grade (Table 1), the assumption that CD151 is involved in cancer progression is well grounded.…”