Centchroman suppresses breast cancer metastasis by reversing epithelial-mesenchymal transition via downregulation of HER2/ERK1/2/MMP-9 signaling

Sajid Khan, Samriddhi Shukla, Sonam Sinha, Amar Deep Lakra, Himangsu K. Bora, Syed Musthapa Meeran

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

Metastatic spread during carcinogenesis worsens disease prognosis and accelerates the cancer progression. Therefore, newer therapeutic options with higher specificity toward metastatic cancer are required. Centchroman (CC), a female oral contraceptive, has previously been reported to possess antiproliferative and proapoptotic activities in human breast cancer cells. Here, we investigated the effect of CC-treatment against breast cancer metastasis and associated molecular mechanism using in vitro and in vivo models. CC significantly inhibited the proliferation of human and mouse mammary cancer cells. CC-treatment also inhibited migration and invasion capacities of highly metastatic MDA-MB-231 and 4T1 cells, at sub-IC50 concentrations. Inhibition of cell migration and invasion was found to be associated with the reversal of epithelial-to-mesenchymal transition (EMT) as observed by the upregulation of epithelial markers and downregulation of mesenchymal markers as well as decreased activities of matrix metalloproteinases. Experimental EMT induced by exposure to TGFβ/TNFα in nontumorigenic human mammary epithelial MCF10A cells was also reversed by CC as evidenced by morphological changes and modulation in the expression levels of EMT-markers. CC-mediated inhibition of cellular migration was, at least partially, mediated through inhibition of ERK1/2 signaling, which was further validated by using MEK1/2 inhibitor (PD0325901). Furthermore, CC-treatment resulted in suppression of tumor growth and lung metastasis in 4T1-syngeneic mouse model. Collectively, our findings suggest that CC-treatment at higher doses specifically induces cellular apoptosis and inhibits cellular proliferation; whereas at lower doses, it inhibits cellular migration and invasion. Therefore, CC could further be developed as an effective drug candidate against metastatic breast cancer.

Original languageEnglish (US)
Pages (from-to)1-16
Number of pages16
JournalInternational Journal of Biochemistry and Cell Biology
Volume58
DOIs
StatePublished - Jan 2015
Externally publishedYes

Keywords

  • Breast cancer
  • Centchroman
  • Epithelial-to-mesenchymal transition
  • Metastasis
  • Migration

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

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