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Activation of estrogen signaling pathways collaborates with loss of Brca1 to promote development of ERα-negative and ERα-positive mammary preneoplasia and cancer

Oncogene volume 27, pages 794–802 (2008)Cite this article

Abstract

BRCA1 can regulate estrogen receptor-α (ERα) activity. This study tested the hypotheses that Brca1 loss in mammary epithelium alters the estrogenic growth response and that exposure to increased estrogen or ERα collaborates with Brca1 deficiency to accelerate preneoplasia and cancer development. Longer ductal extension was found in mammary glands of Brca1f/f;MMTV-Cre mice during puberty as compared to wild-type mice. Terminal end bud differentiation was impaired in Brca1 mutant mice with preservation of prolactin-induced alveolar differentiation. Exogenous estrogen stimulated an abnormal sustained increase in mammary epithelial cell proliferation and the appearance of ERα-negative preneoplasia in postpubertal Brca1 mutant mice. Carcinogenesis was investigated using Brca1f/f;MMTV-Cre mice hemizygous for p53. Exogenous estrogen increased the percentage of mice with multiple hyperplastic alveolar nodules. Targeted conditional ERα overexpression in mammary epithelial cells of mice that were Brca1 mutant and hemizygous for p53 increased the percentage of mice exhibiting multiple hyperplastic nodules, invasive mammary cancers and cancer multiplicity. Significantly more than half of the preneoplasia and cancers were ERα negative even as their initiation was promoted by ERα overexpression.

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Acknowledgements

This study was supported by NIH NCI MAO/RFP NO1-CN-05024 (PAF and LPJ), RO1CA08000 (EMR, PAF and KT), 2T32CA09686-08 (LPJ) and the Susan G Komen Breast Cancer Foundation PDF040244 (LPJ and SA) and PDF0503642 (MTT).

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Author notes

  1. L P Jones

    Present address: 3Current address: Department of Pharmacology and Experimental Therapeutics, University of Maryland Medical School, Baltimore, MD, USA.,

  2. E D Halama

    Present address: 4Current address: Medical College of Virginia Campus of Virginia Commonwealth University School of Medicine, Richmond, VA, USA.,

  3. A Parrish

    Present address: 5Current address: The Jack H Skirball Center for Chemical Biology and Proteomics, The Salk Institute for Biological Studies, La Jolla, CA, USA.,

  4. L P Jones, M T Tilli and S Assefnia: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA

    L P Jones, M T Tilli, S Assefnia, K Torre, E D Halama, A Parrish, E M Rosen & P A Furth

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  1. L P Jones
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Correspondence to P A Furth.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Jones, L., Tilli, M., Assefnia, S. et al. Activation of estrogen signaling pathways collaborates with loss of Brca1 to promote development of ERα-negative and ERα-positive mammary preneoplasia and cancer. Oncogene 27, 794–802 (2008). https://doi.org/10.1038/sj.onc.1210674

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