Targeted disruption of Brca1 in restricted compartments of the mouse mammary epithelia

Smart, Chanel E.; Clarke, Catherine; Brooks, Kelly; Raghavendra, Ashwini; Brewster, Brooke L.; French, Juliet D.; Hetherington, Rehan; Fleming, Jean S.; Rothnagel, Joseph A.; Wainwright, Brandon; Lakhani, Sunil R.; Brown, Melissa A.

doi:10.1007/s10549-007-9859-2

Cited by 8 publications

(8 citation statements)

References 24 publications

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“…This supports our previous hypothesis that luminal progenitor cells, rather than basal or stem cells, are the target of BRCA1-associated tumourigenesis (Lim et al, 2009), which in turn is consistent with our previous studies showing no mammary phenotype when Brca1 is specifically deleted in non-luminal compartments of the mammary gland (Smart et al, 2008).…”

Section: (A) Endogenoussupporting

confidence: 93%

“…All procedures were approved by The University of Queensland Animal Ethics Committee. Mammary gland dissections for RNA and whole-mount analysis were performed as previously described (Smart et al, 2008).…”

Section: Methodsmentioning

confidence: 99%

“…Tumours arising in BRCA1 mutation carriers and Brca1 conditional knockout mice have a distinct histopathological and molecular phenotype, including high grade, high mitotic index and expression of basal and stem cell-associated genes (Lakhani et al, 1998;Sorlie et al, 2003;Liu et al, 2008;Shakya et al, 2008;Wright et al, 2008a, b). It has been suggested that BRCA1-associated tumours arise in the basal or stem cell compartments of the mammary gland (Foulkes et al, 2003), although there is also evidence to suggest that that these characteristics may arise as a consequence of BRCA1 loss in other mammary cell types (Liu et al, 2008;Smart et al, 2008). Although the detailed pathway between BRCA1 disruption and breast tumour development has yet to be fully elucidated, recent findings suggest that tumours arising in human BRCA1 mutation carriers may arise from mammary luminal progenitor cells of the mammary gland (Lim et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Analysis of Brca1-deficient mouse mammary glands reveals reciprocal regulation of Brca1 and c-kit

et al. 2010

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Disruption of the breast cancer susceptibility gene Brca1 results in defective lobular-alveolar development in the mammary gland and a predisposition to breast tumourigenesis in humans and in mice. Recent evidence suggests that BRCA1 loss in humans is associated with an expansion of the luminal progenitor cell compartment in the normal breast and tumours with a luminal progenitorlike expression profile. To further investigate the role of BRCA1 in the mammary gland, we examined the consequences of Brca1 loss in mouse mammary epithelial cells in vitro and in vivo. Here, we show that Brca1 loss is associated with defective morphogenesis of SCp2 and HC11 mouse mammary epithelial cell lines and that in the MMTV-Cre Brca1 Co/Co mouse model of Brca1 loss, there is an accumulation of luminal progenitor (CD61 þ CD29 lo CD24 þ ) cells during pregnancy. By day 1 of lactation, there are marked differences in the expression of 1379 genes, with most significantly altered pathways and networks, including lactation, the immune response and cancer. One of the most differentially expressed genes was the luminal progenitor marker, c-kit. Immunohistochemical analysis revealed that the increase in c-kit levels is associated with an increase in c-kit positivity. Interestingly, an inverse association between Brca1 and c-kit expression was also observed during mammary epithelial differentiation, and small interfering RNA-mediated knockdown of Brca1 resulted in a significant increase in c-kit mRNA levels. We found no evidence that c-kit plays a direct role in regulating differentiation of HC11 cells, suggesting that Brca1-mediated induction of c-kit probably contributes to Brca1-associated tumourigenesis via another cellular process, and that c-kit is likely to be a marker rather than a mediator of defective lobular-alveolar development resulting from Brca1 loss.

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Section: (A) Endogenoussupporting

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Analysis of Brca1-deficient mouse mammary glands reveals reciprocal regulation of Brca1 and c-kit

et al. 2010

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“…K14 is expressed in the basal cells of the mammary gland during embryonic stages and in adulthood. The K14-cre/BRCA1 knockout model did not develop mammary tumors as was observed in the MMTV-cre and WAP-cre counterparts, suggesting that loss of BRCA1 in the K14 expressing basal compartment of mammary ducts is not a factor in the phenotype observed in the MMTV and WAP BRCA1 knockout mice [69]. These studies further highlight the importance of promoter selection in generating conditional knockout mice and the power of tissue and cell type targeting to dissect the relevance of specific tissue compartments in tumor development.…”

Section: Constitutive and Conditional Expression In Transgenic Micementioning

confidence: 77%

“…LOH in p53 was observed in the majority of the tumors in these BRCA1 knockout mice [86]. More recently, Smart et al generated BRCA1 conditional knockout mice using the cre-lox system under the regulation of the keratin 14 (K14) promoter to examined cell type specific knockdown of BRCA1 in the mammary glands [69]. K14 is expressed in the basal cells of the mammary gland during embryonic stages and in adulthood.…”

Section: Constitutive and Conditional Expression In Transgenic Micementioning

confidence: 99%

Transgenic mouse models of hormonal mammary carcinogenesis: Advantages and limitations

Kirma

Tekmal

2012

The Journal of Steroid Biochemistry and Molecular Biology

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Mouse Models of Breast Cancer

Sakamoto

Schmidt

Wagner

2015

Methods in Molecular Biology

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Breast cancer is the most common cause of cancer death in women worldwide. This malignancy is a complex disease, which is defined by an intrinsic heterogeneity on the histopathological and molecular level as well as response to therapy and outcome. In addition to classical histopathological features, breast cancer can be categorized into at least five major subtypes based on comprehensive gene expression profiling: luminal A, luminal B, basal-like, ERBB2-positive, and normal-like breast cancer. Genetically engineered mouse models can serve as tools to study the molecular underpinnings for this disease. Given the genetic complexity that drives the initiation and progression of individual breast cancer subtypes, it is evident that certain models can reflect only particular aspects of this malignancy. In this book chapter, we will primarily focus on advances in modeling breast cancer at defined stages of carcinogenesis using genetically engineered mice. We will discuss the ability as well as shortcomings of these models to faithfully recapitulate the spectrum of human breast cancer subtypes.

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Targeted disruption of Brca1 in restricted compartments of the mouse mammary epithelia

Cited by 8 publications

References 24 publications

Analysis of Brca1-deficient mouse mammary glands reveals reciprocal regulation of Brca1 and c-kit

Analysis of Brca1-deficient mouse mammary glands reveals reciprocal regulation of Brca1 and c-kit

Transgenic mouse models of hormonal mammary carcinogenesis: Advantages and limitations

Mouse Models of Breast Cancer

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