Deciphering the molecular networks that discriminate organ-confined breast cancer from metastatic breast cancer may lead to the identification of critical biomarkers for breast cancer invasion and aggressiveness. Here metabolomics, a global study of metabolites, has been applied to explore the metabolic alterations that characterize breast cancer progression. We profiled a total of 693 metabolites across 87 serum samples related to breast cancer (46 clinically localized and 41 metastatic breast cancer) and 49 normal samples. These unbiased metabolomic profiles were able to distinguish normal individuals, clinically localized and metastatic breast cancer patients. 9-cis-Retinoic acid, an isomer of all-trans retinoic acid, was identified as a differential metabolite that significantly decreased during breast cancer progression to metastasis, and its levels were also reduced in urine samples from biopsy-positive breast cancer patients relative to biopsy-negative individuals and in invasive breast cancer cells relative to benign MCF-10A cells. The addition of exogenous 9-cis-retinoic acid to MDA-MB-231 cells and knockdown of aldehyde dehydrogenase 1 family member A1, a regulatory enzyme for 9-cis-retinoic acid, remarkably impaired cell invasion and migration, presumably through preventing the key regulator cofilin from activation and inhibiting MMP2 and MMP9 expression. Taken together, our study showed the potential inhibitory role for 9-cis-retinoic acid in breast cancer progression by attenuating cell invasion and migration.
Keywords: 9-cis-retinoic acid; breast cancer; invasion; metabolomics; metastatic.
© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.