In turn, LATS phosphorylates the transcriptional co-activators YAP and TAZ (Yorkie-Yki in Drosophila), thereby, limiting their nuclear import 8, 9, 10, 11, 12, 13, 14, 15. In mammals, the canonical Hippo pathway consists of the MST (sterile 20-like kinase) kinases, which activate the LATS1/2 (large tumour suppressor, Warts-Wts in Drosophila) kinases through phosphorylation 7. Among these, the highly conserved Hippo signal transduction pathway, originally discovered in the fruit fly Drosophila melanogaster, has emerged as a critical tumour suppressor pathway in breast cancer 5, 6. During this multistep process, normal breast epithelial cells acquire various cellular properties arising from deregulated cellular signalling 3, 4. Thus, their loss could deem as promising prognostic biomarkers for breast cancer.īreast cancer progression depends on cell autonomous regulatory mechanisms, driven by mutations and epigenetic changes, and on non-cell autonomous interactions with the surrounding tumour microenvironment 1, 2. As the two Dystonin isoforms BPAG1eA and BPAG1e are necessary to inhibit the acquisition of transformed features and are both downregulated in breast tumour samples and in MCF10A cells with conditional induction of the Src proto-oncogene, they could function as the predominant Dystonin tumour suppressor variants in breast epithelial cells. In vivo, the Drosophila Dystonin Short stop also restricts tissue growth by limiting Yorkie activity. Moreover, treating DST-depleted MCF10A cells with the YAP inhibitor Verteporfin prevents their growth. Strikingly, while Dystonin maintains focal adhesion integrity, promotes cell spreading and cell-substratum adhesion, it prevents Zyxin accumulation, stabilizes LATS and restricts YAP activation. We show that in MCF10A cells, Dystonin is necessary to restrain cell growth, anchorage-independent growth, self-renewal properties and resistance to doxorubicin. In this report, we demonstrate that Dystonin is a candidate tumour suppressor in breast cancer and provide an underlying molecular mechanism. However, little is known about its role in carcinogenesis. Aberrant expression of the Spectraplakin Dystonin (DST) has been observed in various cancers, including those of the breast.
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