Maintenance of hormone responsiveness in luminal breast cancers by suppression of Notch

James M. Haughian, Mauricio P. Pinto, J. Chuck Harrell, Brian S. Bliesner, Kristiina M. Joensuu, Wendy W. Dye, Carol A. Sartorius, Aik Choon Tan, Païvi Heikkilä, Charles M. Perou, Kathryn B. Horwitz

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Luminal breast cancers express estrogen (ER) and/or progesterone (PR) receptors and respond to hormone therapies. Basal-like "triple negative" cancers lack steroid receptors but are cytokeratin (CK) 5- positive and require chemotherapy. Here we show that more than half of primary ER +PR + breast cancers contain an ER -PR -CK5 +"luminobasal" subpopulation exceeding 1% of cells. Starting from ER +PR + luminal cell lines, we generated lines with varying luminal to luminobasal cell ratios and studied their molecular and biological properties. In luminal disease, luminobasal cells expand in response to antiestrogen or estrogen withdrawal therapies. The phenotype and gene signature of the hormone-resistant cells matches that of clinical triple negative basal-like and claudin-low disease. Luminobasal cell expansion in response to hormone therapies is regulated by Notch1 signaling and can be blocked by γ-secretase inhibitors. Our data establish a previously unrecognized plasticity of ER +PR + luminal breast cancers that, without genetic manipulation, mobilizes outgrowth of hormone-resistant basal-like disease in response to treatment. This undesirable outcome can be prevented by combining endocrine therapies with Notch inhibition.

Original languageEnglish
Pages (from-to)2742-2747
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number8
DOIs
Publication statusPublished - 2012 Feb 21

Keywords

  • Basal breast cancer
  • Endocrine therapy
  • Estrogen receptor
  • Slug

ASJC Scopus subject areas

  • General

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  • Cite this

    Haughian, J. M., Pinto, M. P., Harrell, J. C., Bliesner, B. S., Joensuu, K. M., Dye, W. W., Sartorius, C. A., Tan, A. C., Heikkilä, P., Perou, C. M., & Horwitz, K. B. (2012). Maintenance of hormone responsiveness in luminal breast cancers by suppression of Notch. Proceedings of the National Academy of Sciences of the United States of America, 109(8), 2742-2747. https://doi.org/10.1073/pnas.1106509108