Abstract

Epithelial-mesenchymal transition (EMT) plays a crucial role in breast cancer metastasis and inhibition of EMT may be an effective approach to suppress metastatic breast cancer. High LRP6 expression is usually observed in breast cancer and predicts poor prognosis. In present study, we investigated whether chlorogenic acid (CA) has an EMT inhibitory effect on breast cell lines and underlying molecular mechanism. We found that CA treatment transformed MCF-7 cell morphology from spindle shape (mesenchymal phenotype) to spherical shape (epithelial phenotype). CA clearly increased epithelial markers' expression (E-cadherin and ZO-1) but decreased mesenchymal markers' expression (ZEB1, N-cadherin, Vimentin, Snail and Slug). In addition, CA attenuated MMP-2 and MMP-9 activities and inhibited cell migration and invasion. CA also down-regulated LRP6 expression, knockdown LRP6 with siRNA repressed cell mobility and invasion while overexpression of LRP6 promoted EMT and antagonized the EMT inhibitory effect of CA on MCF-7 cells. In vivo study showed that CA significantly reduced tumor volume and tumor weight. Immunohistochemical analysis demonstrated that CA inhibited xenograft tumor EMT with LRP6 and Vimentin decreased and E-cadherin increased. In conclusion, CA restrained EMT and invasion of breast cancer through down-regulating LRP6 expression. CA may be developed as an EMT inhibitor for breast cancer treatment.

Significance Statement chlorogenic acid (CA), one of the most common polyphenol compounds in traditional Chinese medicine, repressed EMT and weakens cellular mobility and invasion in MCF-7 cells. The mechanism studies demonstrated that CA inhibits MCF-7 cell EMT and invasion via targeting LRP6. Additionally, CA could inhibit tumor growth and xenograft tumor EMT in vivo. The EMT inhibitory property of CA warrants further studies of CA as a drug candidate for the treatment of metastatic breast cancer.