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Studying Therapy Response and Resistance in Mouse Models for BRCA1-Deficient Breast Cancer

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Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

Worldwide, more than one million women are diagnosed with breast cancer every year, making it the most common malignancy of females in the developed world. Germline mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 account for 4–6% of all breast cancer cases, and mutation carriers have a lifetime risk of 80% for developing breast cancer and 40% for developing ovarian cancer. Current treatment options are limited and often do not lead to cure. In the 17 years since the discovery of BRCA1, the generation of mouse models for BRCA1 deficiency has greatly aided our understanding of it’s role in tumorigenesis. In contrast to human BRCA1 mutation carriers, mice carrying heterozygous mutations in Brca1 did not develop spontaneous tumors. This led to the generation of conditional mouse models in which tissue-specific Brca1 deletion induces formation of mammary tumors that closely resemble human BRCA1-mutated breast tumors. These models have proven useful for studying BRCA1-related tumor development, drug response and resistance. BRCA1-deficient cancer cells are defective in DNA repair mediated by homologous recombination (HR) and therefore highly sensitive to DNA-damaging agents such as platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors. However, BRCA1-mutated tumors can develop resistance to these drugs; hence improved treatment strategies are critical. Existing mouse models have already proven useful for preclinical testing of (combinations of) therapeutic agents that may be beneficial for the treatment of patients with BRCA1-mutated tumors. In this review, we discuss the progress made towards modeling BRCA1-deficient breast cancer in mice and what we have learned from preclinical studies using these models.

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Abbreviations

aCGH:

array comparative genomic hybridization

BRCA1:

breast cancer susceptibility gene 1

BRCA2:

breast cancer susceptibility gene 2

CNA:

copy number alteration

DDR:

DNA damage response

DSBs:

double-strand breaks

ER:

estrogen receptor

ESC:

embryonic stem cell

GEM:

genetically engineered mouse

HER2:

human epidermal growth factor receptor 2

HR:

homologous recombination

MaSCs:

mammary stem cells

PARP:

poly(ADP-ribose) polymerase

P-gp:

P-glycoprotein

PR:

progesterone receptor

TIC:

tumor initiating cell

TNBC:

triple negative breast cancer.

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Acknowledgements

We thank Drs. Karin de Visser and Jonathan Coquet for critical reading of the manuscript. This work is financially supported by grants from the European Commission (FP7 project EuroSyStem), the Dutch Cancer Society (grants NKI 2007–3772 and NKI 2008–4116) and the Center for Translation Molecular medicine (Breast CaRe). E.M was supported by fellowships from the European Commission (Marie Curie fellowship PIIF-GA-2009-237486) and the National Health and Medical Research Council Australia (#575577).

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  1. Division of Molecular Biology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Ewa Malgorzata Michalak & Jos Jonkers

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Correspondence to Jos Jonkers.

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Michalak, E.M., Jonkers, J. Studying Therapy Response and Resistance in Mouse Models for BRCA1-Deficient Breast Cancer. J Mammary Gland Biol Neoplasia 16, 41–50 (2011). https://doi.org/10.1007/s10911-011-9199-z

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