Mouse models of BRCA1 and BRCA2 deficiency: past lessons, current understanding and future prospects

Evers, Bastiaan; Jonkers, Jos

doi:10.1038/sj.onc.1209871

Cited by 222 publications

(218 citation statements)

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“…Our data are most consistent with a model of HBBC oncogenesis in which selected stochastic coding mutation of TP53 in a basal-like breast cancer progenitor cell precedes loss of the second BRCA1 allele, which is known to otherwise be lethal to cells (reviewed in ref. 24 ), and that the subsequent BRCA1-dependent DSB repair defect precipitates genetic disruption of PTEN, which is then clonally selected. This model implies that most BBCs may be addicted 25 to aberrant PTEN-PI3K pathway signaling.…”

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Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair

et al. 2007

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Basal-like breast cancer (BBC) is a subtype of breast cancer with poor prognosis [1][2][3] . Inherited mutations of BRCA1, a cancer susceptibility gene involved in double-strand DNA break (DSB) repair, lead to breast cancers that are nearly always of the BBC subtype [3][4][5] ; however, the precise molecular lesions and oncogenic consequences of BRCA1 dysfunction are poorly understood. Here we show that heterozygous inactivation of the tumor suppressor gene Pten leads to the formation of basal-like mammary tumors in mice, and that loss of PTEN expression is significantly associated with the BBC subtype in human sporadic and BRCA1-associated hereditary breast cancers. In addition, we identify frequent gross PTEN mutations, involving intragenic chromosome breaks, inversions, deletions and micro copy number aberrations, specifically in BRCA1-deficient tumors. These data provide an example of a specific and recurrent Correspondence should be addressed to R.P. (rep15@columbia.edu). 14 These authors contributed equally to this work. AUTHOR CONTRIBUTIONS L.H.S., S.K.G.-S., R.P. and Å.B conceived and designed the study; L.H.S., S.K.G.-S., J.S., G.J., K.H., S.K., J.V.-C., H.O., T.S., L.M., S.P.E., H.H., R.P. and Å.B. collected the samples; L.H.S., K.L., M.J., L.M., T.L., M.S., J.I. and H.H. performed and analyzed immunohistochemistry experiments; L.H.S. and C.P. designed and performed methylation analyses; L.H.S., C.P., M.M. and K.H. performed nucleotide sequencing experiments; L.H.S., J.S., G.J. and K.H. performed and analyzed aCGH experiments; L.H.S., M.M.P., S.S. and V.V.V.S.M. designed and performed FISH experiments; L.H.S., S.K.G.-S. and M.K. performed statistical analyses; R.P. and Å.B. supervised the study; and L.H.S. wrote the paper with assistance from R.P. and Å.B. and input from all coauthors.Note: Supplementary information is available on the Nature Genetics website. [1][2][3][4][5] . Of these, basal-like breast cancer (BBC) comprises 10-20% of all breast cancer and is one of the subtypes with the worst prognosis 2-5 . The term BBC was coined because these tumors express cytokeratin markers typical of basally oriented epithelial cells of the normal mammary gland, such as CK5, CK14 and CK17 (refs. 1,3,5 ). In addition to having characteristic cytokeratin expression, BBCs are highly proliferative, poorly differentiated and genomically unstable, and they pose clinical challenges because they rarely express the three most common therapeutically targeted 'Achilles' heels' of breast cancer: the estrogen receptor (ER), progesterone receptor and HER2 receptor (refs. 1,3,5,7 ).Intriguingly, breast tumors initiated by an inherited mutation of BRCA1 are nearly always basal-like 3,5 . BRCA1 dysfunction is thought to be tumorigenic primarily owing to defective BRCA1-dependent DSB repair, which precipitates an accumulation of secondary mutations 10 ; however, only general genomic patterns at relatively low resolution have been described (reviewed in ref. 5 ). Despite these advances in delineating BBC, the molecu...

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Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair

et al. 2007

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“…This cancer, caused by gene fusions that affect the bone marrow, can now be treated after extensive research using genetically engineered mice (GEMMs) resembling different types of APL. In a similar vein, GEMMs bearing the human breast cancer gene BRCA1 mimicked features of the human breast cancer better than xenograft models and helped in defining a treatment using chemical inhibitors of poly-(ADP-ribose)-polymerase-1, which delays the onset of resistense to the treatment [39]. …”

Section: Preclinical Modelingmentioning

confidence: 99%

Chimeric Antigen Receptor T Cells for the Treatment of Cancer and the Future of Preclinical Models for Predicting their Toxicities

Wegner

2017

Immunotherapy

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CAR-T cell therapy has achieved highly promising results in clinical trials, particulary in B-cell malignancies. However, reports of Serious adverse events (SAE) including a number of patient deaths has raised concerns about safety of this treatment.Presently available pre-clinical models are not designed for predicting toxicities seen in human patients. Besides choosing the right animal model, careful considerations must be taken in CAR T-cell design and the amount of T-cells infused. The development of more sophisticated in vitro models and humanized mouse models for preclinical modeling and toxicity tests will help us to improve the design of clinical trials in cancer immunotherapy.

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“…Until now, a total of 10 different conventional Brca1 mouse mutants have been generated and characterised, each carrying a mutation in a different part of the gene (Xu et al, 1999b;Evers and Jonkers, 2006;Kim et al, 2006). In contrast to women with heterozygous BRCA1 germline mutations, none of the heterozygous Brca1 mouse mutants developed spontaneous mammary tumours.…”

Section: Conventional Brca1 Mouse Modelsmentioning

confidence: 99%

Preclinical mouse models for BRCA1-associated breast cancer

Drost

Jonkers

2009

Br J Cancer

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A substantial part of all hereditary breast cancer cases is caused by BRCA1 germline mutations. In this review, we will discuss the insights into BRCA1 functions that we obtained from mouse models with conventional and conditional mutations in Brca1. The most advanced models closely resemble human BRCA1-related breast cancer and may therefore be useful for addressing clinically relevant questions. Breast cancer is by far the most frequent cancer in women, accounting for over 20% of all cancer cases. Familial breast cancers, including those associated with heterozygous germline mutations in the major susceptibility genes BRCA1 and BRCA2, account for 5 -10% of breast cancer cases in the western world. BRCA1 mutation carriers have a lifetime risk of about 80% for developing breast cancer and a 40% lifetime risk for developing ovarian cancer. Most BRCA1-associated tumours show loss of heterozygosity (LOH) at the BRCA1 locus, leading to loss of the wild-type allele, which is consistent with a tumour suppressor function of BRCA1 (Narod and Foulkes, 2004).Since the discovery of the BRCA1 gene in 1994 (Miki et al, 1994), several genetically engineered mouse models have been generated for studying the in vivo functions of BRCA1. Initial studies used conventional knockout mice with germline mutations in the mouse Brca1 gene. These conventional Brca1 mouse mutants have enabled us to learn a lot about the biological roles of BRCA1. Because of the embryonic lethality of homozygous animals carrying two defective Brca1 alleles and the lack of mammary tumour development in heterozygous mice carrying one defective and one wild-type Brca1 allele, these models could not be used to study the role of BRCA1 in tumorigenesis. To overcome these problems, the investigators generated conditional Brca1 knockout mice that enable tissue-specific inactivation of BRCA1 by Cre recombinase-mediated deletion of one or more Brca1 exons flanked by loxP recombination sites (Jonkers and Berns, 2002). The most recently developed conditional Brca1 mammary tumour models closely mimic several important aspects of human BRCA1-associated breast cancer and therefore serve as important tools for the development of novel therapies for this disease. Before elaborating on the Brca1 conventional and conditional mouse models that have been generated to date, we will discuss the characteristics of human BRCA1-related breast cancer in more detail.

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Mouse models of BRCA1 and BRCA2 deficiency: past lessons, current understanding and future prospects

Cited by 222 publications

References 111 publications

Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair

Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair

Chimeric Antigen Receptor T Cells for the Treatment of Cancer and the Future of Preclinical Models for Predicting their Toxicities

Preclinical mouse models for BRCA1-associated breast cancer

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