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Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
10:36

Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer

Published on: March 17, 2016

Activation of the Src/p21ras/Erk pathway by progesterone receptor via cross-talk with estrogen receptor

A Migliaccio1, D Piccolo, G Castoria

  • 1Istituto di Patologia Generale e Oncologia, Facoltà di Medicina e Chirurgia, II Università di Napoli, Largo S.Aniello a Caponapoli, 2, 80138 Napoli, Italy.

The EMBO Journal
|June 6, 1998
PubMed

Insights

Progestins and estrogens, ovarian hormones, stimulate breast cancer cell growth by activating the Src/p21(ras)/Erk pathway. This cross-talk between hormones, mediated by the estrogen receptor, is crucial for tumor proliferation.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Oncology

Background:

  • Estrogen receptor (ER) interaction with c-Src activates the Src/p21(ras)/Erk pathway in breast cancer.
  • The precise mechanisms by which ovarian hormones stimulate breast tumor growth remain incompletely understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying progestin-stimulated breast cancer cell proliferation.
  • To investigate the cross-talk between progesterone receptor (PR) and estrogen receptor (ER) signaling pathways.

Main Methods:

  • Utilized human breast cancer T47D cells and Cos-7 cells co-transfected with ER and progesterone receptor B (PRB).
  • Assessed pathway activation via MAP kinase assays.
  • Investigated protein-protein interactions using co-immunoprecipitation and identified interaction domains.

Main Results:

  • Progestins activate the Src/p21(ras)/Erk pathway in T47D cells, an effect blocked by anti-progestins and anti-estrogens.
  • Progestin activation of MAP kinase pathway in Cos-7 cells requires co-transfection of ER.
  • A transcriptionally inactive PRB mutant activates the pathway, indicating non-transcriptional effects.
  • PRB associates with ER via its N-terminal 168 amino acids, not c-Src, and this association is essential for pathway activation.

Conclusions:

  • Progesterone receptor signaling activates the Src/p21(ras)/Erk pathway indirectly through interaction with the estrogen receptor.
  • Estrogen receptor acts as a conduit for progestin-induced signals to the Src/p21(ras)/Erk pathway.
  • Unrecognized cross-talk between ovarian hormones plays a critical role in promoting cancer cell growth.

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