BRCA1 Inhibition of Estrogen Receptor Signaling in Transfected Cells

Fan, Saijun; Wang, J.-A.; Yuan, Ray-Hwang; Ma, Yanfen; Meng, Qinghui; Erdos, Michael R.; Pestell, Richard G.; Fang, Yuan; Auborn, Karen J.; Goldberg, Itzhak D.; Rosen, Eliot M.

doi:10.1126/science.284.5418.1354

Cited by 450 publications

(356 citation statements)

References 20 publications

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“…Rescue of the inhibition of ER-a by I3C and/or genistein is consistent with previous studies showing that wtBRCA1 inhibits ER-a signalling and a DN-BRCA1 rescues the inhibition (Fan et al, 1999b;2001a, b). However, the finding that BRCA1-siRNA stimulates AR activity and partially reverses the inhibition of DHT-induced AR activity by I3C and genistein is somewhat surprising, since wtBRCA1 and wtBRCA2 were reported to stimulate AR signalling (Yeh et al, 2000;Shin and Verma, 2003).…”

Section: Discussionsupporting

confidence: 91%

“…To express BRCA2, a full-length human BRCA2 cDNA (provided by Dr Qingshen Gao, New England Medical Center, Boston, MA, USA) was cloned into the pCMV-Tag2B vector (Stratagene). The human ER-a expression vector and the oestrogen-responsive reporter ERE-TK-Luc were described before (Fan et al, 1999b(Fan et al, , 2001a. Wild-type AR expression vector pSG5-AR and the androgen-responsive reporter plasmid ARE-TK-Luc were provided by Dr Chawshang Chang (University of Rochester, Rochester, NY, USA).…”

Section: Expression Vectors and Reporter Plasmidsmentioning

confidence: 99%

“…Oestrogen receptor-a activity was measured via transient transfection assays, using an oestrogen-responsive luciferase reporter (Fan et al, 1999b(Fan et al, , 2001a. Briefly, subconfluent proliferating cells in 24-well dishes were cotransfected overnight with a wild-type ER-a expression vector (pSG5-ER-a) and the ERE-TK-Luc reporter (0.25 mg of each plasmid per well), in the presence of Lipofectaminet (Life Technologies, Carlsbad, CA, USA).…”

Section: Cell Viability (Mtt) Assaysmentioning

confidence: 99%

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BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells

et al. 2006

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Indole-3-carbinol (I3C) and genistein are naturally occurring chemicals derived from cruciferous vegetables and soy, respectively, with potential cancer prevention activity for hormone-responsive tumours (e.g., breast and prostate cancers). Previously, we showed that I3C induces BRCA1 expression and that both I3C and BRCA1 inhibit oestrogen (E2)-stimulated oestrogen receptor (ER-a) activity in human breast cancer cells. We now report that both I3C and genistein induce the expression of both breast cancer susceptibility genes (BRCA1 and BRCA2) in breast (MCF-7 and T47D) and prostate (DU-145 and LNCaP) cancer cell types, in a time-and dosedependent fashion. Induction of the BRCA genes occurred at low doses of I3C (20 mM) and genistein (0.5 -1.0 mM), suggesting potential relevance to cancer prevention. A combination of I3C and genistein gave greater than expected induction of BRCA expression. Studies using small interfering RNAs (siRNAs) and BRCA expression vectors suggest that the phytochemical induction of BRCA2 is due, in part, to BRCA1. Functional studies suggest that I3C-mediated cytoxicity is, in part, dependent upon BRCA1 and BRCA2. Inhibition of E2-stimulated ER-a activity by I3C and genistein was dependent upon BRCA1; and inhibition of ligand-inducible androgen receptor (AR) activity by I3C and genistein was partially reversed by BRCA1-siRNA. Finally, we provide evidence suggesting that the phytochemical induction of BRCA1 expression is due, in part, to endoplasmic reticulum stress response signalling. These findings suggest that the BRCA genes are molecular targets for some of the activities of I3C and genistein.

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Section: Discussionsupporting

confidence: 91%

Section: Expression Vectors and Reporter Plasmidsmentioning

confidence: 99%

Section: Cell Viability (Mtt) Assaysmentioning

confidence: 99%

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BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells

et al. 2006

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“…In 1999, we reported that BRCA1 inhibits the transcriptional activity of ER-a, the major estrogen receptor in breast epithelial cells (Fan et al, 1999a). This inhibition was selective, since BRCA1 failed to inhibit the activities of other sequence-specific transcription factors, including Sp1, E2F-1, c-Fos, and c-Jun.…”

Section: Regulation Of Transcriptionmentioning

confidence: 99%

BRCA1 gene in breast cancer

Rosen

Fan

Pestell

et al. 2003

Journal Cellular Physiology

241

195

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The BRCA1 gene was identified and cloned in 1994 based on its linkage to early onset breast cancer and breast-ovarian cancer syndromes in women. While inherited mutations of BRCA1 are responsible for about 40-45% of hereditary breast cancers, these mutations account for only 2-3% of all breast cancers, since the BRCA1 gene is rarely mutated in sporadic breast cancers. However, BRCA1 expression is frequently reduced or absent in sporadic cancers, suggesting a much wider role in mammary carcinogenesis. Since BRCA1 was cloned in 1994, its molecular function has been the subject of intense investigation. These studies have revealed multiple functions of the BRCA1 that may contribute to its tumor suppressor activity, including roles in: cell cycle progression, several highly specialized DNA repair processes, DNA damage-responsive cell cycle checkpoints, regulation of a set of specific transcriptional pathways, and apoptosis. Many of these functions are linked to protein:protein interactions involving different portions of the 1,863 amino acid (aa) BRCA1 protein. BRCA1 functions in cell cycle progression and the DNA damage response appear to be regulated by distinct and specific phosphorylation events, but the molecular pathways activated by these phosphorylations are only beginning to be unraveled. In addition, the reason that BRCA1 mutation carriers develop specific tumor types (breast and ovarian cancers in women and possibly prostate cancers in men) is not clearly understood. Elucidation of the precise molecular functions of the BRCA1 gene product will greatly enhance our understanding of the pathogenesis of hereditary as well as sporadic mammary carcinogenesis.

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“…A number of investigations performed in cultured cells revealed that BRCA1 specifically inhibits estrogen/ERa transcription activation in either estrogen-dependent (Fan et al, 1999) or estrogenindependent ways (Zheng et al, 2001). It was reported recently that BRCA1 inhibits estrogen biosynthesis through modulating aromatase expression in ovarian granulosa cells (Hu et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

A role of estrogen/ERα signaling in BRCA1-associated tissue-specific tumor formation

Xiao

et al. 2007

Oncogene

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Estrogen and its receptor alpha (ERa) have been implicated in the tissue-specific tumorigenesis associated with BRCA1 mutations. However, the majority of breast cancers developed in human BRCA1 mutation carriers are ERa-negative, challenging the link between BRCA1 and estrogen/ERa in breast cancer formation. Using a mouse model lacking the full-length form of BRCA1, here we show that ERa 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 ERa-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/ERa signals in BRCA1-associated tissue-specific tumor formation, and identify several key elements in the estrogen/ERasignaling cascade that can serve as potential therapeutic targets for BRCA1-associated tumorigenesis.

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BRCA1 Inhibition of Estrogen Receptor Signaling in Transfected Cells

Cited by 450 publications

References 20 publications

BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells

BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells

BRCA1 gene in breast cancer

A role of estrogen/ERα signaling in BRCA1-associated tissue-specific tumor formation

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