Tetraspanin CD151 is increasingly implicated as a multifaceted mediator of
cancer development and progression. Here we investigated the role of CD151 in
breast cancer in the context of the Wnt oncogenic activation. Our data showed that removal of one or both of CD151 alleles in the MMTV-Wnt1 model significantly decreased the
tumor-free survival of mice from 34 weeks on average to 22 weeks and 18 weeks, respectively. This effect coincided with an accelerated
tumor growth and an increased number of Ki-67+ proliferative cells. Mechanistically, the CD151-deficient
tumors were largely ER+, and exhibited hyperactivation of the Wnt pathway as reflected by a marked upregulation in β-
catenin and
Cyclin D1, and their target genes. In addition,
E-cadherin displayed a cytosolic distribution and
transcription factor Snail was markedly upregulated. Collectively, this data implies that CD151 suppresses the Wnt1-driven
tumorigenesis, at least in part, via counteracting the epithelial-mesenchymal transition (EMT)-like program in
luminal epithelial cells. Meanwhile, the proportion of
tumor cells expressing CK5 or p63, the
biomarkers of myoepithelial/basal cells, markedly decreased in the absence of CD151. This change was accompanied by a decreased invasiveness of
tumors and their incompetence to form a long-term cell culture. Consistent with this basal cell-linked role, the CD151 downregulation impairs mammosphere formation in MCF-10A cells and the defect was rescued by re-expression of intact CD151 ORF, but not its
integrin binding-defective mutant. Overall, our study suggests that CD151 is a key player in the Wnt oncogene-driven
tumorigenesis and impacts
breast cancer malignancy in a cell type-dependent manner.