Signaling inputs to progesterone receptor gene regulation and promoter selectivity

Mol Cell Endocrinol. 2009 Sep 24;308(1-2):47-52. doi: 10.1016/j.mce.2009.01.004. Epub 2009 Jan 20.

Abstract

Progesterone receptors (PR) select and control genetic programs in the breast during normal mammary gland development, and progestin-driven processes contribute to the initiation and/or progression of breast cancer [Beral, V., 2003. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 362, 419-427; Chlebowski, R.T., Hendrix, S.L., Langer, R.D., Stefanick, M.L., Gass, M., Lane, D., Rodabough, R.J., Gilligan, M.A., Cyr, M.G., Thomson, C.A., et al., 2003. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA 289, 3243-3253]. Throughout the mammalian life span, progesterone exerts varying biological consequences on the mammary epithelial compartment, from brief proliferative spurts that occur with each luteal phase of the menstrual cycle to the massive expansion of the pregnant gland in preparation for lactation [Brisken, C., Park, S., Vass, T., Lydon, J.P., O'Malley, B.W., Weinberg, R.A., 1998. A paracrine role for the epithelial progesterone receptor in mammary gland development. Proc. Natl. Acad. Sci. U.S.A. 95, 5076-5081; Ismail, P.M., Amato, P., Soyal, S.M., DeMayo, F.J., Conneely, O.M., O'Malley, B.W., Lydon, J.P., 2003. Progesterone involvement in breast development and tumorigenesis-as revealed by progesterone receptor "knockout" and "knockin" mouse models. Steroids 68, 779-787]. These processes, while important developmentally, can become deregulated in breast cancer, thereby contributing to unchecked proliferation, increased survival, and invasive behaviors. Recently, our lab has focused on the molecular mechanisms, including phosphorylation events, by which PRs select specific target genes in response to progestins and other mitogenic hormonal signals (i.e. EGF, heregulin). Herein, we discuss the actions of cytoplasmic signaling molecules such as c-Src and mitogen-activated protein kinases as key mediators of PR promoter selectivity.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Breast Neoplasms / metabolism
  • Female
  • Gene Expression Regulation*
  • Humans
  • Mitogen-Activated Protein Kinases
  • Pregnancy
  • Progestins / metabolism
  • Promoter Regions, Genetic*
  • Protein Processing, Post-Translational
  • Receptors, Progesterone / genetics
  • Receptors, Progesterone / metabolism*
  • Signal Transduction / physiology*
  • Sp1 Transcription Factor / genetics
  • Sp1 Transcription Factor / metabolism
  • Transcription, Genetic

Substances

  • Progestins
  • Receptors, Progesterone
  • Sp1 Transcription Factor
  • Mitogen-Activated Protein Kinases