Low‐Dose Farnesyltransferase Inhibitor Suppresses HIF‐1α and Snail Expression in Triple‐Negative Breast Cancer MDA‐MB‐231 Cells In Vitro

• Published in: Journal of cellular physiology Vol. 232; no. 1; pp. 192 - 201
• Main Authors: Tanaka, Tomokazu, Ikegami, Yuichi, Nakazawa, Harumasa, Kuriyama, Naohide, Oki, Miwa, Hanai, Jun‐ichi, Sukhatme, Vikas P., Kaneki, Masao
• Format: Journal Article
• Language: English
• Published: United States 01.01.2017
• Subjects: Cadherins - metabolism; Cell Line, Tumor; Cell Proliferation - physiology; Farnesyltranstransferase - antagonists & inhibitors; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Quinolones - pharmacology; Receptor, Epidermal Growth Factor - metabolism; Receptors, Estrogen - metabolism; Signal Transduction - drug effects; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.25411

The aggressiveness of triple‐negative breast cancer (TNBC), which lacks estrogen receptor, progesterone receptor and epidermal growth factor receptor 2 (HER2), represents a major challenge in breast cancer. Migratory and self‐renewal capabilities are integral components of invasion, metastasis and recurrence of TNBC. Elevated hypoxia‐inducible factor‐1α (HIF‐1α) expression is associated with aggressiveness of cancer. Nonetheless, how HIF‐1α expression is regulated and how HIF‐1α induces aggressive phenotype are not completely understood in TNBC. The cytotoxic effects of farnesyltransferase (FTase) inhibitors (FTIs) have been studied in cancer and leukemia cells. In contrast, the effect of FTIs on HIF‐1α expression has not yet been studied. Here, we show that clinically relevant low‐dose FTI, tipifarnib (300 nM), decreased HIF‐1α expression, migration and tumorsphere formation in human MDA‐MB‐231 TNBC cells under a normoxic condition. In contrast, the low‐dose FTIs did not inhibit cell growth and activity of the Ras pathway in MDA‐MB 231 cells. Tipifarnib‐induced decrease in HIF‐1α expression was associated with amelioration of the Warburg effect, hypermetabolic state, increases in Snail expression and ATP release, and suppressed E‐cadherin expression, major contributors to invasion, metastasis and recurrence of TBNC. These data suggest that FTIs may be capable of ameliorating the aggressive phenotype of TNBC by suppressing the HIF‐1α‐Snail pathway. J. Cell. Physiol. 232: 192–201, 2017. © 2016 Wiley Periodicals, Inc. HIF‐1α and Snail play important roles in metastatic and invasive phenotypes in triple‐negative breast cancer (TNBC). Low‐dose farnesyltransferase inhibitor (FTI) reduced HIF‐1α and Snail expression in TNBC MDA‐MB‐231 cells. In association with the suppression of the HIF‐1α‐Snail pathway, low‐dose FTI decreased migration and sphere formation capabilities in vitro with little, if any, inhibition of the Ras pathway and cell growth in MDA‐MB‐231 cells.