Steroid induction of therapy-resistant cytokeratin-5-positive cells in estrogen receptor-positive breast cancer through a BCL6-dependent mechanism. Oncogene 2016 Mar 17;35(11):1373-85
Date
06/23/2015Pubmed ID
26096934Pubmed Central ID
PMC4800289DOI
10.1038/onc.2015.193Scopus ID
2-s2.0-84932182008 (requires institutional sign-in at Scopus site) 25 CitationsAbstract
Therapy resistance remains a major problem in estrogen receptor-α (ERα)-positive breast cancer. A subgroup of ERα-positive breast cancer is characterized by mosaic presence of a minor population of ERα-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 ERα 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 ERα-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 ERα+/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 ERα-positive breast cancers.
Author List
Goodman CR, Sato T, Peck AR, Girondo MA, Yang N, Liu C, Yanac AF, Kovatich AJ, Hooke JA, Shriver CD, Mitchell EP, Hyslop T, Rui HMESH terms used to index this publication - Major topics in bold
AldosteroneAnimals
Antineoplastic Agents
Breast Neoplasms
Cell Line, Tumor
Cell Proliferation
DNA-Binding Proteins
Dexamethasone
Doxorubicin
Drug Resistance, Neoplasm
Estrogen Receptor alpha
Female
Gene Expression Regulation, Neoplastic
Glucocorticoids
Humans
Hyaluronan Receptors
Keratin-5
MCF-7 Cells
Mice
Mice, Nude
Mineralocorticoids
Neoplasm Recurrence, Local
Neoplasm Transplantation
Progestins
Prognosis
Prolactin
Proto-Oncogene Proteins c-bcl-6
RNA Interference
RNA, Small Interfering
Receptors, Progesterone
Tamoxifen
Transplantation, Heterologous
Up-Regulation
