BRCA1-associated mammary tumorigenesis is dependent on estrogen rather than progesterone signaling

J Pathol. 2018 Sep;246(1):41-53. doi: 10.1002/path.5105. Epub 2018 Jul 4.

Abstract

Hereditary breast cancers in BRCA1 mutation carriers are mostly estrogen receptor α (ERα)-negative and progesterone receptor (PR)-negative; however, hormone depletion via bilateral oophorectomy does result in a marked reduction in breast cancer risk, suggesting that BRCA1-associated breast tumorigenesis is dependent on hormone signaling. We used geneticaly engineered mouse models to determine the individual influences of ERα and PR signaling on the development of BRCA1-deficient breast cancer. In line with the human data, BRCA1-deficient mouse mammary tumors are ERα-negative, and bilateral ovariectomy leads to abrogation of mammary tumor development. Hormonal replacement experiments in ovariectomized mice showed that BRCA1-deficient mammary tumor formation is promoted by estrogen but not by progesterone. In line with these data, mammary tumorigenesis was significantly delayed by the selective ERα downregulator fulvestrant, but not by the selective PR antagonist Org33628. Together, our results illustrate that BRCA1-associated tumorigenesis is dependent on estrogen signaling rather than on progesterone signaling, and call into question the utility of PR antagonists as a tumor prevention strategy for BRCA1 mutation carriers. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords: BRCA1; breast cancer; hormone receptor antagonists; hormone signaling; ovariectomy.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • BRCA1 Protein
  • Carcinoma in Situ / chemically induced*
  • Carcinoma in Situ / genetics
  • Carcinoma in Situ / metabolism
  • Carcinoma in Situ / pathology
  • Cell Proliferation / drug effects
  • Cell Transformation, Neoplastic / chemically induced*
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Drug Implants
  • Estradiol / administration & dosage
  • Estradiol / toxicity*
  • Estrenes / pharmacology
  • Estrogen Receptor Antagonists / pharmacology
  • Estrogen Receptor alpha / drug effects
  • Estrogen Receptor alpha / metabolism
  • Estrogen Receptor beta / drug effects
  • Estrogen Receptor beta / metabolism
  • Estrogen Replacement Therapy / adverse effects*
  • Female
  • Fulvestrant / pharmacology
  • Mammary Neoplasms, Experimental / chemically induced*
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology
  • Mice, 129 Strain
  • Mice, Transgenic
  • Ovariectomy
  • Progesterone / administration & dosage
  • Progesterone / toxicity*
  • Receptors, Progesterone / drug effects
  • Receptors, Progesterone / metabolism
  • Signal Transduction / drug effects*
  • Time Factors
  • Tumor Burden / drug effects
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics*

Substances

  • BRCA1 Protein
  • Brca1 protein, mouse
  • Drug Implants
  • Estrenes
  • Estrogen Receptor Antagonists
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Receptors, Progesterone
  • Tumor Suppressor Proteins
  • Fulvestrant
  • Progesterone
  • Estradiol
  • Org 33628