Breast cancer
2007/4/30/10
Arterioscler Thromb Vasc Biol. 2007 Apr 19; [Epub
ahead of print] Loss-of-Function Deletion
of the Steroid Receptor Coactivaor-1 Gene in Mice Reduces Estrogen Effect
on the Vascular Injury Response. Department of Molecular and
Cellular Biology, Baylor 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. GRP78/BiP Inhibits
Endoplasmic Reticulum BIK and Protects Human Breast Cancer Cells against
Estrogen Starvation-Induced Apoptosis. Department of Biochemistry and
Molecular Biology, USC/Norris Comprehensive Cancer Center, 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. 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, 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]
