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Breast Cancer Research and Treatment

, Volume 94, Issue 2, pp 171–183 | Cite as

Progesterone Pre-treatment Potentiates EGF Pathway Signaling in The Breast Cancer Cell Line ZR-75*

  • A. Carvajal
  • N. Espinoza
  • S. Kato
  • M. Pinto
  • A. Sadarangani
  • C. Monso
  • E. Aranda
  • M. Villalon
  • J. K. Richer
  • K. B. Horwitz
  • J. J. Brosens
  • G. I. OwenEmail author
Report

Summary

Progesterone in hormone replacement therapy (HRT) preparations increases, while hysterectomy greatly reduces, the incidence of breast cancer. Cross-talk between the progesterone and growth factor signaling pathways occurs at multiple levels and this maybe a key factor in breast cancer survival and progression. To test this hypothesis, we characterized the effect of progesterone pre-treatment on the sensitization of the epidermal growth factor (EGF) signaling pathway to EGF in the breast cancer cell line ZR-75. For the first time in ZR-75 cells and in agreement with previous work using synthetic progestins, we demonstrate that pre-treatment with the natural ligand progesterone increases EGF receptor (EGFR) levels and subsequent ligand-dependent phosphorylation. Downstream we demonstrate that progesterone alone increases erk-1 + 2 phosphorylation, potentiates EGF-phosphorylated erk-1 + 2 and maintains these levels elevated for 24 h; over 20 h longer than in vehicle treated cells. Additionally, progesterone increased the levels of STAT5, another component of the EGF signaling cascade. Progesterone increased EGF mediated transcription of a c-fos promoter reporter and the nuclear localization of the native c-fos protein. Furthermore, progesterone and EGF both alone and in combination, significantly increase cell proliferation. Several results presented herein demonstrate the conformity between the action of the natural ligand progesterone with that of synthetic progestins such as MPA and R5020 and allows the postulation that the progestin/progesterone-dependent increase of EGF signaling provides a survival advantage to burgeoning cancer cells and may contribute to the breast cancer risk associated with endogenous progesterone and with progestin-containing HRT.

Keywords

c-fos EGFR erk HRT progestin STAT5 

Abbreviations

C

vehicle control

EGF

epidermal growth factor

EGFR

EGF receptor

ER

estrogen receptor

hours

h

HRT

hormone replacement therapy

minutes

min

P4

Progesterone

PR

progesterone receptor

STAT

signal transducers and activators of transcription

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Copyright information

© Springer 2005

Authors and Affiliations

  • A. Carvajal
    • 1
  • N. Espinoza
    • 1
  • S. Kato
    • 1
  • M. Pinto
    • 1
  • A. Sadarangani
    • 1
  • C. Monso
    • 1
  • E. Aranda
    • 1
  • M. Villalon
    • 1
  • J. K. Richer
    • 2
  • K. B. Horwitz
    • 2
  • J. J. Brosens
    • 3
  • G. I. Owen
    • 1
    Email author
  1. 1.Unidad de Reproducción y Desarrollo, Facultad de Ciencias BiológicasPontificia Universidad Católica de ChileSantiagoChile
  2. 2.Department of Medicine, Division of EndocrinologyUniversity of Colorado Health Sciences CenterDenverUSA
  3. 3.Imperial College London, Hammersmith HospitalInstitute of Reproductive and Developmental Biology, LondonUnited Kingdom

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