Mouse models of BRCA1 and their application to breast cancer research

Cancer Metastasis Rev (2013) 32:2537

DOI 10.1007/s10555-012-9403-7

Mouse models of BRCA1 and their application to breast cancer research

Jennifer Dine & Chu-Xia Deng

Published online: 24 October 2012# Springer Science+Business Media New York (outside the USA) 2012

Abstract Germline mutations of human breast cancer-associated gene 1 (BRCA1) predispose women to breast and ovarian cancers. In mice, over 20 distinct mutations, including null, hypomorphic, isoform, conditional, and point mutations, have been created to study functions of Brca1 in mammary development and tumorigenesis. Analyses using these mutant mice have yielded an enormous amount of information that greatly facilitates our understanding of the gender- and tissue-specific tumor suppressor functions of BRCA1, as well as enriches our insights into applying these preclinical models of disease to breast cancer research. Here, we review features of these mutant mice and their applications to cancer prevention and therapeutic treatment.

Keywords BRCA1 . Breast cancer . Disease mechanism . Modeling . Therapy

1 Introduction

In Western countries, breast cancer occurs at high frequency and affects one in eight women during their lifetime. In 2011, 230,480 new cases of invasive breast cancers and 39,520 breast cancer deaths were anticipated to occur among American women [1]. While the majority of breast cancers are caused by genetic alterations of somatic cells of the breast, approximately 8 % of cases are inherited, which may be caused by tumor suppressor mutations. Through

linkage analysis of families with early-onset breast cancer disease, Hall et al. (1990) mapped the first candidate cancer susceptibility gene in chromosome 17q21 [2]. This gene was named the breast cancer associated gene 1 (BRCA1) and was subsequently cloned in 1994 [3]. It has been estimated that loss of function mutations in BRCA1 contribute to approximately half of all familial breast cancer cases and 90 % of combined familial breast/ovarian cancers [47]. Currently, over 800 mutations and sequence variants have been found in the BRCA1 coding region (http://research.nhgri.nih.gov/bic

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Web End =bic ), although the functional relevance of many of them remains elusive.

The human BRCA1 gene encodes a large protein of 1,863 amino acids, while the full-length mouse Brca1 protein contains 1,812 amino acids [3, 8]. Due to alternative splicing or aberrant transcriptional termination [912], BRCA1 also encodes two major isoforms of...