Centchroman suppresses breast cancer metastasis by reversing epithelial–mesenchymal transition via downregulation of HER2/ERK1/2/MMP-9 signaling |
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| Institution: | 2. Massachusetts General Hospital, Division of Hematology-Oncology, Department of Medicine, Boston, MA;1. Dept. of Genetics, Animal Biology Group, Faculty of Natural Science, University of Tabriz, Tabriz, Iran;2. Department of Biology, Tabriz Branch of Islamic Azad University, Tabriz, Iran;3. Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran;4. Department of Molecular Medicine, Pasteur Institute of Iran, Tehran, Iran;5. Department of General & Vascular Surgery, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran;1. Roger Williams Medical Center, Providence, RI 02908;2. USC Keck School of Medicine, Los Angeles, CA 90033;3. Sieber Plastic Surgery, San Francisco, CA 94904;4. Dallas Plastic Surgery Institute, Dallas, TX 75231;5. UT Southwestern Department of Plastic Surgery, Dallas 75205;6. Bacchi Pathology Laboratory, San Paolo, Brazil 18602-010;7. Inst Bras Controle Câncer, San Paolo, Brazil 04536-010;8. Plastic Surgery Division, MD Anderson Cancer Center, Houston, TX 77030;9. Hematopathology Division, MD Anderson Cancer Center, Houston, TX 77030;1. Department of Hepatobiliary Surgery, The First People''s Hospital of Yunnan Province, Kuming 650030, Yunnan, China;2. Department of Gastroenterology, Liaocheng People''s Hospital, Liaocheng, Shandong Province, 252000, China;3. Department of infectious diseases, The First People''s Hospital of Yunnan Province, Kuming 650030, Yunnan, China;4. DICAT Biomedical Computation Centre, Vancouver, BC, Canada |
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| 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. |
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| Keywords: | Centchroman Breast cancer Epithelial-to-mesenchymal transition Metastasis Migration |
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