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

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.

[1]  M. Erdos,et al.  p300 Modulates the BRCA1 inhibition of estrogen receptor activity. , 2002, Cancer research.

[2]  M. Tilli,et al.  Introduction of estrogen receptor-alpha into the tTA/TAg conditional mouse model precipitates the development of estrogen-responsive mammary adenocarcinoma. , 2003, The American journal of pathology.

[3]  C J Wright,et al.  Estrogen receptor status in breast cancer. , 1980, Canadian journal of surgery. Journal canadien de chirurgie.

[4]  E. Rosen,et al.  BRCA1 Inhibits Membrane Estrogen and Growth Factor Receptor Signaling to Cell Proliferation in Breast Cancer , 2004, Molecular and Cellular Biology.

[5]  G. Silberstein.  Postnatal mammary gland morphogenesis , 2001, Microscopy research and technique.

[6]  Adrian V. Lee,et al.  Progesterone crosstalks with insulin-like growth factor signaling in breast cancer cells via induction of insulin receptor substrate-2 , 2003, Oncogene.

[7]  Steven E. Bayer,et al.  A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. , 1994, Science.

[8]  Susan L Neuhausen,et al.  Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. , 2002, The New England journal of medicine.

[9]  R. Shiu,et al.  Growth Factors in Mammary Gland Development and Function , 1987 .

[10]  J. Ryś,et al.  Lack of synergy between estrogen and progesterone on local IGF-I, IGFBP-3 and IGFBP-2 secretion by both hormone-dependent and hormone-independent breast cancer explants in vitro. Effect of tamoxifen and mifepristone (RU 486). , 2005, Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society.

[11]  D. Hanahan,et al.  Chronic estrogen-induced cervical and vaginal squamous carcinogenesis in human papillomavirus type 16 transgenic mice. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[12]  B. Asch,et al.  Methods in Mammary Gland Biology and Breast Cancer Research , 2000, Springer US.

[13]  W. Ruan,et al.  Progesterone stimulates mammary gland ductal morphogenesis by synergizing with and enhancing insulin-like growth factor-I action. , 2005, Endocrinology.

[14]  Wen-Hwa Lee,et al.  Removal of BRCA1/CtIP/ZBRK1 repressor complex on ANG1 promoter leads to accelerated mammary tumor growth contributed by prominent vasculature. , 2006, Cancer cell.

[15]  F. Miller,et al.  Nontransgenic models of breast cancer. , 2000, Breast cancer research : BCR.

[16]  K. Korach,et al.  Mammary Gland Development and Tumorigenesis in Estrogen Receptor Knockout Mice , 1997, Journal of Mammary Gland Biology and Neoplasia.

[17]  F. Couch,et al.  Effect of pregnancy as a risk factor for breast cancer in BRCA1/BRCA2 mutation carriers , 2005, International journal of cancer.

[18]  M. E. El Etreby,et al.  Additive effect of mifepristone and tamoxifen on apoptotic pathways in MCF-7 human breast cancer cells , 1998, Breast Cancer Research and Treatment.

[19]  C. Deng,et al.  Multiple genetic changes are associated with mammary tumorigenesis in Brca1 conditional knockout mice , 2001, Oncogene.

[20]  L. En.  Human Insulin Receptor Substrate-2 (IRS-2) Is a Primary Progesterone Response Gene , 1999 .

[21]  Zhiyuan Hu,et al.  Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors , 2007, Genome Biology.

[22]  Y. Li,et al.  Prevention of Brca1-Mediated Mammary Tumorigenesis in Mice by a Progesterone Antagonist , 2006, Science.

[23]  Minglin Li,et al.  Promotion of mammary cancer development by tamoxifen in a mouse model of Brca1-mutation-related breast cancer , 2005, Oncogene.

[24]  O. Olopade,et al.  Estrogen Receptor Status in BRCA1- and BRCA2-Related Breast Cancer , 2004, Clinical Cancer Research.

[25]  C. Deng,et al.  Effect of bilateral oophorectomy on mammary tumor formation in BRCA1 mutant mice. , 2005, Oncology reports.

[26]  M. Trivett,et al.  Brca1 inactivation induces p27Kip1-dependent cell cycle arrest and delayed development in the mouse mammary gland , 2004, Oncogene.

[27]  L. Hennighausen,et al.  Spatial and temporal expression of the Cre gene under the control of the MMTV-LTR in different lines of transgenic mice , 2001, Transgenic Research.

[28]  L. Klein-Hitpass,et al.  Human insulin receptor substrate-2 (IRS-2) is a primary progesterone response gene. , 1999, Molecular endocrinology.

[29]  M. Cazzaniga,et al.  Breast Cancer Prevention Trials Using Retinoids , 2004, Journal of Mammary Gland Biology and Neoplasia.

[30]  M. Neville,et al.  The Mammary gland : development, regulation, and function , 1987 .

[31]  A. Ashworth,et al.  The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability , 2006, Oncogene.

[32]  S. Furuta,et al.  Depletion of BRCA1 impairs differentiation but enhances proliferation of mammary epithelial cells. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[33]  J. Rosen,et al.  Stop! In the name of transforming growth factor-β: keeping estrogen receptor-α-positive mammary epithelial cells from proliferating , 2006, Breast Cancer Research.

[34]  L. Chodosh,et al.  Deregulated estrogen receptor alpha expression in mammary epithelial cells of transgenic mice results in the development of ductal carcinoma in situ. , 2005, Cancer research.

[35]  A. Zubel,et al.  The impact of progesterone on simultaneous, local secretion of IGFBP-3 and IGF-I [IGFBP-3/IGF-I index] by human malignant and non-malignant breast explants depends on tissue steroid receptor phenotype. , 2003, Ginekologia polska.

[36]  S. Haslam,et al.  Mammary Gland Growth and Development from the Postnatal Period to Postmenopause: Ovarian Steroid Receptor Ontogeny and Regulation in the Mouse , 2004, Journal of Mammary Gland Biology and Neoplasia.

[37]  X. Coumoul,et al.  Absence of the full-length breast cancer-associated gene-1 leads to increased expression of insulin-like growth factor signaling axis members. , 2006, Cancer research.

[38]  S. Haslam,et al.  Printed in U.S.A. Copyright © 1999 by The Endocrine Society A Mouse Model to Study the Effects of Hormone Replacement Therapy on Normal Mammary Gland during Menopause: Enhanced Proliferative Response to Estrogen in Late Postmenopausal Mice* , 2022 .

[39]  E. Rosen,et al.  The breast cancer susceptibility gene BRCA1 regulates progesterone receptor signaling in mammary epithelial cells. , 2006, Molecular endocrinology.

[40]  L. Hennighausen,et al.  Cre-mediated gene deletion in the mammary gland. , 1997, Nucleic acids research.

[41]  P. Furth,et al.  Validation of transgenic models of breast cancer: ductal carcinoma in situ (DCIS) and Brca1-mutation-related breast cancer. , 2005, Breast cancer online : BCO.

[42]  Thomas Ried,et al.  Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation , 1999, Nature Genetics.