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

  1. Gregg L. Semenzaa,b,d,e,f,g,h,1
  1. aVascular Program, Institute for Cell Engineering,
  2. bMcKusick-Nathans Institute of Genetic Medicine, and
  3. Departments of dPediatrics,
  4. eMedicine,
  5. fOncology,
  6. gRadiation Oncology, and
  7. hBiological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and
  8. cDepartment of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China

  1. Contributed by Gregg L. Semenza, November 10, 2014 (sent for review October 10, 2014; reviewed by Maria Alfonsina Desiderio and Youcef M. Rustum)

Significance

Breast cancer stem cells play essential roles in tumor growth, maintenance, and recurrence after chemotherapy. We report that treatment of human breast cancer cells with chemotherapy results in an enrichment of breast cancer stem cells among the surviving cells, which is dependent upon the activity of hypoxia-inducible factors (HIFs). Studies in mouse tumor models suggest that combining chemotherapy with drugs that block HIF activity may improve the survival of breast cancer patients.

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 resistance 1. 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.

Footnotes

  • ↵1To whom correspondence should be addressed. Email: gsemenza{at}jhmi.edu.

  • Author contributions: D.S. and G.L.S. designed research; D.S., D.M.G., P.C., and L.X. performed research; D.S. and G.L.S. analyzed data; and D.S. and G.L.S. wrote the paper.

  • Reviewers: M.A.D., University of Milan School of Medicine; and Y.M.R., Roswell Park Cancer Institute.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1421438111/-/DCSupplemental.

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