Abstract

In the past year, we have carefully examined ER-alpha expression in our BRCA1 mutant mice. We found that mammary glands of BRCA1 mutant mice displayed higher levels of ER-alpha, and that ER-alpha is highly expressed in the premalignant mammary gland and initiation stages of tumorigenesis, although its expression is gradually diminished during mammary tumor progression. We demonstrate that the absence of full-length BRCA1 increases sensitivity of cells to estrogen-induced extracellular signal-regulated kinase 1/2 phosphorylation and cyclin D1 expression. The absence of BRCA1 turns the proliferation of ER-alpha-positive cells from a paracrine fashion to an autocrine or endocrine fashion. Consequently, BRCA1-mutant cells are sensitized to estrogen-induced cell proliferation in vitro and mammary tumorigenesis in vivo. These findings illustrate a molecular mechanism for estrogen/ER-alpha signals in BRCA1-associated tissue-specific tumor formation, and identify several key elements in the estrogen/ER-alpha-signaling cascade that can serve as potential therapeutic targets for BRCA1-associated tumorigenesis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Intramural Research (Z01)
Project #
1Z01DK056008-01
Application #
7593702
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2007
Total Cost
$265,073
Indirect Cost

  Institution

Name
National Institute of Diabetes and Digestive and Kidney Diseases
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

Yan, Fang; Polk, D Brent (2012) Characterization of a probiotic-derived soluble protein which reveals a mechanism of preventive and treatment effects of probiotics on intestinal inflammatory diseases. Gut Microbes 3:25-8
Yan, Fang; Polk, D Brent (2012) Lactobacillus rhamnosus GG: An Updated Strategy to Use Microbial Products to Promote Health. Funct Food Rev 4:77-84
Goettel, Jeremy A; Liang, Dongchun; Hilliard, Valda C et al. (2011) KSR1 is a functional protein kinase capable of serine autophosphorylation and direct phosphorylation of MEK1. Exp Cell Res 317:452-63
Yan, Fang; Cao, Hanwei; Cover, Timothy L et al. (2011) Colon-specific delivery of a probiotic-derived soluble protein ameliorates intestinal inflammation in mice through an EGFR-dependent mechanism. J Clin Invest 121:2242-53
Yan, Fang; Polk, D B (2011) Probiotics and immune health. Curr Opin Gastroenterol 27:496-501
Yan, Fang; Polk, David Brent (2010) Probiotics: progress toward novel therapies for intestinal diseases. Curr Opin Gastroenterol 26:95-101
Yan, Fang; Cao, Hanwei; Chaturvedi, Rupesh et al. (2009) Epidermal growth factor receptor activation protects gastric epithelial cells from Helicobacter pylori-induced apoptosis. Gastroenterology 136:1297-1307, e1-3
Li, Bin; Vincent, Alicia; Cates, Justin et al. (2009) Low levels of tumor necrosis factor alpha increase tumor growth by inducing an endothelial phenotype of monocytes recruited to the tumor site. Cancer Res 69:338-48
Li, Wenmei; Sandhoff, Roger; Kono, Mari et al. (2007) Depletion of ceramides with very long chain fatty acids causes defective skin permeability barrier function, and neonatal lethality in ELOVL4 deficient mice. Int J Biol Sci 3:120-8
Li, W; Xiao, C; Vonderhaar, B K et al. (2007) A role of estrogen/ERalpha signaling in BRCA1-associated tissue-specific tumor formation. Oncogene 26:7204-12

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