Flowchart: Preparation: ER

Text Box: Bik

Text Box:  Src-1

Text Box: EstrogenText Box: BipText Box: Grp78

Text Box: Mmp-1Text Box: pS2

Breast cancer

Text Box: Estrogen receptor

Text Box: Er-betaText Box: Er-alpha





Arterioscler Thromb Vasc Biol. 2007 Apr 19; [Epub ahead of print]Click here to read  Links

Loss-of-Function Deletion of the Steroid Receptor Coactivaor-1 Gene in Mice Reduces Estrogen Effect on the Vascular Injury Response.

     Yuan Y, Xu J.

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Tex.

OBJECTIVE: The steroid receptor coactivator-1 (SRC-1) is a transcriptional coactivator for nuclear receptors including estrogen receptor (ER). SRC-1 can interact with ER in an estrogen binding-dependent manner to potentiate the transcriptional activity of ER. Previous studies showed that SRC-1 was required for the full function of ER in cultured cells and in the reproductive system. In this study, we have tested the hypothesis that SRC-1 is required for the inhibition of neointima formation by estrogen in a vascular wall. METHODS AND RESULTS: The expression of SRC-1 protein in the vascular wall was examined by immunoblotting and immunohistochemistry. Wild-type and SRC-1 null mice were ovariectomized, and then unilateral ligation of the carotid artery was performed to induce neointima growth in these mice. Mice were treated with placebo or estrogen. Neointima growth near the ligation site was examined and quantitatively analyzed. These experiments demonstrated that SRC-1 was expressed in the endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and neointima cells. The neointima growth induced by the ligation of common carotid artery was almost completely inhibited by estrogen in wild-type mice, but was only partially inhibited in SRC-1-null mice. Further analysis revealed that the blunted inhibition of neointima formation by estrogen was attributed to a less inhibition of neointimal cell proliferation. CONCLUSIONS: SRC-1 is expressed in ECs, VSMCs, and neointima cells. SRC-1 expression in these cells facilitates estrogen/ER-mediated vasoprotection through the inhibition of neointima formation after a vascular injury.

PMID: 17446438 [PubMed - as supplied by publisher

Cancer Res. 2007 Apr 15;67(8):3734-40.Click here to read  Links

GRP78/BiP Inhibits Endoplasmic Reticulum BIK and Protects Human Breast Cancer Cells against Estrogen Starvation-Induced Apoptosis.

     Fu Y, Li J, Lee AS.

Department of Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, California.

The recent development of hormonal therapy that blocks estrogen synthesis represents a major advance in the treatment of estrogen receptor-positive breast cancer. However, cancer cells often acquire adaptations resulting in resistance. A recent report reveals that estrogen starvation-induced apoptosis of breast cancer cells requires BIK, an apoptotic BH3-only protein located primarily at the endoplasmic reticulum (ER). Searching for novel partners that interact with BIK at the ER, we discovered that BIK selectively forms complex with the glucose-regulated protein GRP78/BiP, a major ER chaperone with prosurvival properties naturally induced in the tumor microenvironment. GRP78 overexpression decreases apoptosis of 293T cells induced by ER-targeted BIK. For estrogen-dependent MCF-7/BUS breast cancer cells, overexpression of GRP78 inhibits estrogen starvation-induced BAX activation, mitochondrial permeability transition, and consequent apoptosis. Further, knockdown of endogenous GRP78 by small interfering RNA (siRNA) sensitizes MCF-7/BUS cells to estrogen starvation-induced apoptosis. This effect was substantially reduced when the expression of BIK was also reduced by siRNA. Our results provide the first evidence that GRP78 confers resistance to estrogen starvation-induced apoptosis in human breast cancer cells via a novel mechanism mediated by BIK. These results further suggest that GRP78 expression level in the tumor cells may serve as a prognostic marker for responsiveness to hormonal therapy based on estrogen starvation and that combination therapy targeting GRP78 may enhance efficacy and reduce resistance. [Cancer Res 2007;67(8):3734-40].

PMID: 17440086 [PubMed - in process]


Cancer Res. 2007 Apr 15;67(8):3955-62.Click here to read  Links

Estrogen Receptor {beta}2 Negatively Regulates the Transactivation of Estrogen Receptor {alpha} in Human Breast Cancer Cells.

     Zhao C, Matthews J, Tujague M, Wan J, Strom A, Toresson G, Lam EW, Cheng G, Gustafsson JA, Dahlman-Wright K.

Department of Biosciences and Nutrition, Novum, Karolinska Institutet, Huddinge, Sweden.

Estrogens, by binding to and activating two estrogen receptors (ERalpha and ERbeta), are critically involved in the development of the mammary gland and breast cancer. An isoform of ERbeta, ERbeta2 (also called ERbetacx), with an altered COOH-terminal region, is coexpressed with ERalpha in many human breast cancers. In this study, we generated a stable cell line from MCF7 breast cancer cells expressing an inducible version of ERbeta2, along with endogenous ERalpha, and examined the effects of ERbeta2 on the ERalpha protein levels and function. We showed that ERbeta2 inhibited ERalpha-mediated transactivation via estrogen response element and activator protein-1 sites of reporter constructs as well as the endogenous genes pS2 and MMP-1. Chromatin immunoprecipitation assays revealed that ERbeta2 expression caused a significant reduction in the recruitment of ERalpha to both the pS2 and MMP-1 promoters. Furthermore, ERbeta2 expression induced proteasome-dependent degradation of ERalpha. The inhibitory effects of ERbeta2 on ERalpha activity were further confirmed in HEK293 cells that lack functional endogenous ERs. We also showed that ERbeta2 can interact with ERalpha both in vitro and in mammalian cells, which is compatible with a model where ERbeta2/ERalpha heterodimers are targeted to the proteasome. Finally, in human breast cancer samples, we observed that expression of ERbeta2 significantly correlated with ERalpha-negative phenotype. Our data suggest that ERbeta2 could influence ERalpha-mediated effects relevant for breast cancer development, including hormone responsiveness. [Cancer Res 2007;67(8):3955-62].

PMID: 17440111 [PubMed - in process]