title: Low-Dose Farnesyltransferase Inhibitor Suppresses HIF-1α and Snail Expression in Triple-Negative Breast Cancer MDA-MB-231 Cells In Vitro.
abstract: 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.
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ikegami
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.|Shriners Hospitals for Children, Boston, Massachusetts.
authors.forename: Harumasa
authors.initials: H
authors.lastname: Nakazawa
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.|Shriners Hospitals for Children, Boston, Massachusetts.
authors.forename: Naohide
authors.initials: N
authors.lastname: Kuriyama
authors.affiliation: Division of Nephrology, Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Miwa
authors.initials: M
authors.lastname: Oki
authors.affiliation: Division of Nephrology, Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Hanai
authors.affiliation: Division of Nephrology, Division of Interdisciplinary Medicine and Biotechnology, Department of Medicine, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Vikas P
authors.initials: VP
authors.lastname: Sukhatme
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts. mkaneki@helix.mgh.harvard.edu.|Shriners Hospitals for Children, Boston, Massachusetts. mkaneki@helix.mgh.harvard.edu.
authors.forename: Masao
authors.initials: M
authors.lastname: Kaneki
mesh_terms: D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D066246:ErbB Receptors / Q000378:metabolism*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D015363:Quinolones / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism*
chemical_list: D015820:Cadherins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015363:Quinolones; D011960:Receptors, Estrogen; D051231:Farnesyltranstransferase; D066246:ErbB Receptors; C402769:tipifarnib