Hypoxia-inducible factors are required for chemotherapy resistance of breast cancer stem cells

Debangshu Samanta, Daniele M. Gilkesa, Pallavi Chaturvedia, Lisha Xiang, Gregg L. Semenza

Research output: Contribution to journalArticle

Abstract

Triple negative breast cancers (TNBCs) are defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 expression, and are treated with cytotoxic chemotherapy such as paclitaxel or gemcitabine, with a durable response rate of less than 20%. TNBCs are enriched for the basal subtype gene expression profile and the presence of breast cancer stem cells, which are endowed with self-renewing and tumor-initiating properties and resistance to chemotherapy. Hypoxia-inducible factors (HIFs) and their target gene products are highly active in TNBCs. Here, we demonstrate that HIF expression and transcriptional activity are induced by treatment of MDA-MB-231, SUM-149, and SUM-159, which are human TNBC cell lines, as well as MCF-7, which is an ER+/PR+ breast cancer line, with paclitaxel or gemcitabine. Chemotherapy-induced HIF activity enriched the breast cancer stem cell population through interleukin-6 and interleukin-8 signaling and increased expression of multidrug resistance1. Coadministration of HIF inhibitors overcame the resistance of breast cancer stem cells to paclitaxel or gemcitabine, both in vitro and in vivo, leading to tumor eradication. Increased expression of HIF-1α or HIF target genes in breast cancer biopsies was associated with decreased overall survival, particularly in patients with basal subtype tumors and those treated with chemotherapy alone. Based on these results, clinical trials are warranted to test whether treatment of patients with TNBC with a combination of cytotoxic chemotherapy and HIF inhibitors will improve patient survival.

Original languageEnglish (US)
Pages (from-to)E5429-E5438
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number50
DOIs
StatePublished - Dec 16 2014

Keywords

  • Digoxin
  • Mammary fat pad implantation
  • Tumor relapse

ASJC Scopus subject areas

  • General

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