Prolactin suppresses a progestin-induced CK5-positive cell population in luminal breast cancer through inhibition of progestin-driven BCL6 expression

T. Sato, T. H. Tran, A. R. Peck, M. A. Girondo, C. Liu, C. R. Goodman, L. M. Neilson, B. Freydin, I. Chervoneva, T. Hyslop, A. J. Kovatich, J. A. Hooke, C. D. Shriver, S. Y. Fuchs, H. Rui

Research output: Contribution to journalArticle

Abstract

Prolactin controls the development and function of milk-producing breast epithelia but also supports growth and differentiation of breast cancer, especially luminal subtypes. A principal signaling mediator of prolactin, Stat5, promotes cellular differentiation of breast cancer cells in vitro, and loss of active Stat5 in tumors is associated with antiestrogen therapy failure in patients. In luminal breast cancer, progesterone induces a cytokeratin-5 (CK5)-positive basal cell-like population. This population possesses characteristics of tumor stem cells including quiescence, therapy resistance and tumor-initiating capacity. Here we report that prolactin counteracts induction of the CK5-positive population by the synthetic progestin (Pg) R5020 in luminal breast cancer cells both in vitro and in vivo. CK5-positive cells were chemoresistant as determined by fourfold reduced rate of apoptosis following docetaxel exposure. Pg-induction of CK5 was preceded by marked upregulation of BCL6, an oncogene and transcriptional repressor critical for the maintenance of leukemia-initiating cells. Knockdown of BCL6 prevented induction of CK5-positive cell population by Pg. Prolactin suppressed Pg-induced BCL6 through Jak2-Stat5 but not Erk- or Akt-dependent pathways. In premenopausal but not postmenopausal patients with hormone receptor-positive breast cancer, tumor protein levels of CK5 correlated positively with BCL6, and high BCL6 or CK5 protein levels were associated with unfavorable clinical outcome. Suppression of Pg-induction of CK5-positive cells represents a novel prodifferentiation effect of prolactin in breast cancer. The present progress may have direct implications for breast cancer progression and therapy as loss of prolactin receptor-Stat5 signaling occurs frequently and BCL6 inhibitors currently being evaluated for lymphomas may have value for breast cancer.

Original languageEnglish (US)
Pages (from-to)2215-2224
Number of pages10
JournalOncogene
Volume33
Issue number17
DOIs
StatePublished - Apr 24 2014

Keywords

  • BCL6
  • CK5
  • Stat5
  • breast cancer
  • progesterone
  • prolactin

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Sato, T., Tran, T. H., Peck, A. R., Girondo, M. A., Liu, C., Goodman, C. R., Neilson, L. M., Freydin, B., Chervoneva, I., Hyslop, T., Kovatich, A. J., Hooke, J. A., Shriver, C. D., Fuchs, S. Y., & Rui, H. (2014). Prolactin suppresses a progestin-induced CK5-positive cell population in luminal breast cancer through inhibition of progestin-driven BCL6 expression. Oncogene, 33(17), 2215-2224. https://doi.org/10.1038/onc.2013.172