Abstract
Metastasis is the main cause of death in cancer patients, including breast cancer (BC). Despite recent progress in understanding the biological and molecular determinants of BC metastasis, effective therapeutic treatments are yet to be developed. Among the multitude of molecular mechanisms that regulate cancer metastasis, the epithelial-to-mesenchymal transition (EMT) program plays a key role in the activation of the biological steps leading to the metastatic phenotype. Kindlin-2 has been associated with the pathogenesis of several types of cancers, including BC. The role of Kindlin-2 in the regulation of BC metastasis, and to a lesser extent in EMT is not well understood. In this study, we show that Kindlin-2 is closely associated with the development of the metastatic phenotype in BC. We report that knockout of Kindlin-2 in either human or mouse BC cells, significantly inhibits metastasis in both human and mouse models of BC metastasis. We also report that the Kindlin-2-mediated inhibition of metastasis is the result of inhibition of expression of key molecular markers of the EMT program. Mechanistically, we show that miR-200b, a master regulator of EMT, directly targets and inhibits the expression of Kindlin-2, leading to the subsequent inhibition of EMT and metastasis. Together, our data support the targeting of Kindlin-2 as a therapeutic strategy against BC metastasis.
Highlights
Metastasis is the leading cause for cancer-related death worldwide, including breast cancer (BC)-related mortalities[1]
Our recently published study has shown that Kindlin-2 is overexpressed in aggressive human and mouse breast cancer cells and tumours, and that Kindlin-2 is required for primary tumour growth in both human and murine BC models[13]
In the MDA-MB-231 BC model, we found the number of lung nodules, which represent the metastasis foci, was reduced by more than 10-fold (p < 0.01) in mice implanted with the Kindlin2-deficient (Kindlin-2 CRISPR) cells compared to their control (Scram CRISPR) counterparts (Fig. 3A,B)
Summary
Metastasis is the leading cause for cancer-related death worldwide, including breast cancer (BC)-related mortalities[1]. We show that Kindlin-2 is involved in the process of BC metastatic colonization to the lung by regulating the EMT program downstream of miR-200b. We previously reported that expression levels of Kindlin-2 are increased in the more aggressive, highly metastatic human and murine breast cancer (BC) cell lines and in human and mouse BC progression series. MiR-200b targets and regulates Kindlin-2 expression through a conserved seed sequence in the 3′UTR in both the human and mouse FERM2 genes, and expression levels of miR-200b inversely correlate with that of Kindlin-2 and with the aggressiveness of BC cell lines. Overexpression of miR-200b in MDA-MB-231 and 4T1 cells inhibited Kindlin-2 expression, concomitant with downregulation of EMT genes, while it resulted in a significant reduction of the metastatic burden in vivo. Our data provide the underpinnings of a new signalling axis, in which miR-200b regulates Kindlin-2, which in turn regulates EMT, thereby suggesting a novel role of Kindlin-2 in the regulation of BC progression and metastasis
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