Brca1 regulates in vitro differentiation of mammary epithelial cells

Kubista, Marion; Rosner, Margit; Kubista, E.; Bernaschek, Gerhard; Hengstschläger, Markus

doi:10.1038/sj.onc.1205580

Cited by 55 publications

(49 citation statements)

References 40 publications

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“…Accumulation of luminal progenitor cells in the mammary glands of MMTV-Cre Brca1 Co/Co mice during pregnancy Brca1 has been shown to play an important role in mouse mammary epithelial differentiation in vitro (Kubista et al, 2002). To confirm and extend previous studies, we examined the consequences of Brca1 suppression in two mouse mammary epithelial cell lines HC11 and SCp2, and examined the morphological and cellular changes in the mammary glands of MMTV-Cre Brca1 Co/Co mice.…”

Section: Resultsmentioning

confidence: 70%

“…Disruption of the breast cancer susceptibility gene BRCA1 results in defects in mammary epithelial differentiation in vitro (Kubista et al, 2002;Furuta et al, 2005) and defective lobular-alveolar development in the mammary gland in vivo, based on analysis of breast tissue from BRCA1 mutation carriers or mice in which the Brca1 gene has been deleted from the mammary gland or in which the mammary gland expresses a dominant-negative Brca1 mutant (Jernstrom et al, 1998;Xu et al, 1999;Russo et al, 2001;Brown et al, 2002;Triplett et al, 2008). 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).…”

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: Resultsmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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“…In reproductive tissue, Brca1 is an estrogen-sensitive gene ( 13,38 ), however, in the gastrocnemius muscle of mice we detected greater levels of both the full-length and short [Brca1 ⌬ 11, 85 kDa as previously defi ned ( 26 )] Brca1 splice variants in males compared with females ( Fig. 1D ).…”

Section: Brca1 Expression In Mouse Skeletal Musclementioning

confidence: 67%

“…A previous investigation has shown BRCA1 mRNA is expressed in C2C12 myoblasts, which would suggest a possible role in skeletal muscle ( 13 ). However, to our knowledge, no studies have mechanistically examined the role of BRCA1 in skeletal muscle.…”

Section: Immunoblotting Analysismentioning

confidence: 89%

BRCA1 is a novel regulator of metabolic function in skeletal muscle

Jackson

Gidlund

Norrbom

et al. 2014

Journal of Lipid Research

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This article is available online at http://www.jlr.org breast cancer and/or tumorigenesis in reproductive tissues ( 3 ). The BRCA1 gene produces either a full-length breast cancer type 1 susceptibility protein (BRCA1) or through alternatively splicing two documented variants, BRCA1 ⌬ 11 or BRCA1 ⌬ 11b, both of which lack a nuclear localization signal ( 4 ). Recently, BRCA1 was identifi ed as a regulator of lipid metabolism in human breast cancer cells (MCF7) as a result of direct interaction with the phosphorylated form of acetylCoA carboxylase (ACC-p) at the BRCA1 C-terminal (BRCT) domains ( 5, 6 ). The interaction encourages the maintenance of the phosphorylated state of ACC thereby altering lipid metabolism in the cancer cell line ( 5, 6 ).ACC has two isoforms, ACC1 or ACC2, with ACC2 containing an extra 146 amino acids in the NH 2 -terminal region. ACC activity is negatively regulated by phosphorylation of residue Ser 79 on ACC1 and Ser 221 on ACC2 ( 7,8 ). In the active form (i.e., dephosphorylated), ACC catalyzes the carboxylation of acetyl-CoA into malonyl-CoA (MaCoA). Changes in cellular MaCoA content alter intracellular lipid dynamics in two specifi c manners ( 9, 10 ). MaCoA directly contributes to de novo synthesis of palmitate via FAS and MaCoA also allosterically inhibits carnitine palmitoyltransferase-1 (CPT-1), a mitochondrial long chain fatty acid transporter ( 11 ). Thus, in mammary tissue the ability of BRCA1 to affect ACC activity alters cellular lipid concentrations by indirectly regulating rates of fatty acid synthesis and/or the fl ux of fatty acids into the mitochondria.Abstract Breast cancer type 1 (BRCA1) susceptibility protein is expressed across multiple tissues including skeletal muscle. The overall objective of this investigation was to defi ne a functional role for BRCA1 in skeletal muscle using a translational approach. For the fi rst time in both mice and humans, we identifi ed the presence of multiple isoforms of BRCA1 in skeletal muscle. In response to an acute bout of exercise, we found increases in the interaction between the native forms of BRCA1 and the phosphorylated form of acetyl-CoA carboxylase. Decreasing BRCA1 content using a shRNA approach in cultured primary human myotubes resulted in decreased oxygen consumption by the mitochondria and increased reactive oxygen species production. The decreased BRCA1 content also resulted in increased storage of intracellular lipid and reduced insulin signaling. These results indicate that BRCA1 plays a critical role in the regulation of metabolic function in skeletal muscle. Collectively, these data reveal BRCA1 as a novel target to consider in our understanding of metabolic function and risk for development of metabolic-based diseases. -Jackson, K. C., E-K. Gidlund, J. Abbreviations: ACC, acetyl-CoA carboxylase; ACC-p, phosphorylated form of acetyl-CoA carboxylase; AICAR, 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide; AMPK, AMP-activated protein kinase; BRCA1, Breast Cancer 1, early onset; BRCA1 MG KO, mammary gland tissue fr...

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“…This result suggests that the activation of p53 expression downstream of C/EBP␦ in the mammary gland is indirect and/or requires additional signals. Expression of Brca1 and Brca2, two genes associated with proliferation and differentiation (Kubista et al, 2002), was suppressed by p53 but not by C/EBP␦, suggesting that the decline of BRCA1and BRCA2 on day 1 of mammary gland involution is mediated by p53. This data is in agreement with the ability of p53 to repress the Brca1 promoter (MacLachlan et al, 2000), and the frequent co-regulation of these two genes (Rajan et al, 1997).…”

Section: C/ebp␦ ␦ Is Sufficient To Initiate Involution-specific Eventmentioning

confidence: 92%

C/EBPδ is a crucial regulator of pro-apoptotic gene expression during mammary gland involution

et al. 2005

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The STAT3 transcription factor is an important initiator of mammary gland involution in the mouse. This work shows that the STAT3 target gene CCAAT/enhancer binding protein delta (C/EBP␦ ␦) is a crucial mediator of proapoptotic gene expression events in mammary epithelial cells. In the absence of C/EBP␦ ␦, involution is delayed, the pro-apoptotic genes encoding p53, BAK, IGFBP5 and SGP2/clusterin are not activated, while the anti-apoptotic genes coding for BFL1 and Cyclin D1 are not repressed. Consequently, p53 targets such as survivin, BRCA1, BRCA2 and BAX are not regulated appropriately and protease activation is delayed. Furthermore, expression of MMP3 and C/EBP␤ ␤ during the second phase of involution is perturbed in the absence of C/EBP␦ ␦. In HC11 cells, C/EBP␦ ␦ alone is sufficient to induce IGFBP5 and SGP2. It also suppresses Cyclin D1 expression and cooperates with p53 to elicit apoptosis. This study places C/EBP␦ ␦ between STAT3 and several pro-and anti-apoptotic genes promoting the physiological cell death response in epithelial cells at the onset of mammary gland involution.

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Brca1 regulates in vitro differentiation of mammary epithelial cells

Cited by 55 publications

References 40 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

BRCA1 is a novel regulator of metabolic function in skeletal muscle

C/EBPδ is a crucial regulator of pro-apoptotic gene expression during mammary gland involution

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