Androgen-induced human breast cancer cell proliferation is mediated by discrete mechanisms in estrogen receptor-alpha-positive and -negative breast cancer cells

J Steroid Biochem Mol Biol. 2009 Feb;113(3-5):182-8. doi: 10.1016/j.jsbmb.2008.12.010. Epub 2008 Dec 30.

Abstract

Androgens have important physiological effects in women. Not only are they the precursor hormones for estrogen biosynthesis in the ovaries and extragonadal tissues, but also act directly via androgen receptors (ARs) throughout the body. Studies of the role of androgens on breast cancer development are controversial and the mechanisms involved are not fully understood. In this report we demonstrate that a non-aromatizable androgen metabolite, dihydrotestosterone (DHT), stimulated cell proliferation in vitro of both estrogen receptor-alpha (ER-alpha)-positive MCF-7 cells and ER-alpha-negative MDA-MB-231 human breast cancer cells. A contribution of ER to the proliferative effect of DHT in MCF-7 cells was supported by actions of small interfering RNA (siRNA) ER-alpha transfection and of the specific inhibitor of ER, ICI 182,780 to block DHT-induced proliferation. A contribution of the possible conversion of DHT to androstane-3alpha, 17beta-diol was not excluded in these MCF-7 cell studies. In MDA-MB-231 cells, a novel mechanism was implicated, in that anti-integrin alphavbeta3 or an Arg-Gly-Asp (RGD) peptide targeted at a small molecule binding domain of the integrin eliminated the DHT effect on cell proliferation. Anti-integrin alphavbeta3 did not affect DHT action on MCF-7 cells. A contribution from classical androgen receptor to the DHT effect in each cell line was excluded. A proliferative DHT signal is transduced in both ER-alpha-positive and ER-alpha-negative breast cancer cells, but by discrete mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Antagonists / pharmacology
  • Androgens / metabolism
  • Androgens / pharmacology*
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor / metabolism
  • Cell Proliferation / drug effects*
  • Estradiol / analogs & derivatives
  • Estradiol / pharmacology
  • Estrogen Antagonists / pharmacology
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Female
  • Flutamide / pharmacology
  • Fulvestrant
  • Humans
  • Integrin alphaVbeta3 / metabolism
  • Oligopeptides / pharmacology
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism

Substances

  • AR protein, human
  • Androgen Antagonists
  • Androgens
  • Estrogen Antagonists
  • Estrogen Receptor alpha
  • Integrin alphaVbeta3
  • Oligopeptides
  • RNA, Small Interfering
  • Receptors, Androgen
  • arginyl-glycyl-glutamic acid
  • estrogen receptor alpha, human
  • Fulvestrant
  • Estradiol
  • Flutamide
  • arginyl-glycyl-aspartic acid