4.8 Article

Steroid induction of therapy-resistant cytokeratin-5-positive cells in estrogen receptor-positive breast cancer through a BCL6-dependent mechanism

Journal

ONCOGENE
Volume 35, Issue 11, Pages 1373-1385

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2015.193

Keywords

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Funding

  1. Susan G Komen [KG091116]
  2. Ladies of Port Richmond
  3. NCI [CA185918, CA188575, 1P30CA56036]
  4. Commonwealth University Research Enhancement Program grant with the Pennsylvania Department of Health

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Therapy resistance remains a major problem in estrogen receptor-alpha (ER alpha)-positive breast cancer. A subgroup of ER alpha-positive breast cancer is characterized by mosaic presence of a minor population of ER alpha-negative cancer cells expressing the basal cytokeratin-5 (CK5). These CK5-positive cells are therapy resistant and have increased tumor-initiating potential. Although a series of reports document induction of the CK5-positive cells by progestins, it is unknown if other 3-ketosteroids share this ability. We now report that glucocorticoids and mineralocorticoids effectively expand the CK5-positive cell population. CK5-positive cells induced by 3-ketosteroids lacked ER alpha and progesterone receptors, expressed stem cell marker, CD44, and displayed increased clonogenicity in soft agar and broad drug-resistance in vitro and in vivo. Upregulation of CK5-positive cells by 3-ketosteroids required induction of the transcriptional repressor BCL6 based on suppression of BCL6 by two independent BCL6 small hairpin RNAs or by prolactin. Prolactin also suppressed 3-ketosteroid induction of CK5+ cells in T47D xenografts in vivo. Survival analysis with recursive partitioning in node-negative ER alpha-positive breast cancer using quantitative CK5 and BCL6 mRNA or protein expression data identified patients at high or low risk for tumor recurrence in two independent patient cohorts. The data provide a mechanism by which common pathophysiological or pharmacologic elevations in glucocorticoids or other 3-ketosteroids may adversely affect patients with mixed ER alpha+/CK5+ breast cancer. The observations further suggest a cooperative diagnostic utility of CK5 and BCL6 expression levels and justify exploring efficacy of inhibitors of BCL6 and 3-ketosteroid receptors for a subset of ER alpha-positive breast cancers.

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