The Breast Cancer Susceptibility Gene BRCA1 Regulates Progesterone Receptor Signaling in Mammary Epithelial Cells

Ma, Yanfen; Katiyar, Pragati; Jones, Laundette P.; Fan, Saijun; Zhang, Yiyu; Furth, Priscilla A.; Rosen, Eliot M.

doi:10.1210/me.2004-0488

Cited by 111 publications

(90 citation statements)

References 59 publications

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“…Pushing margins have been found in BRCA1 mutation-positive patients with breast cancer (Lakhani, 1999). Interestingly, a recent publication has cited an association between BRCA1 mutation and increased progesterone receptor signalling (Ma et al, 2006). This would be in keeping with our findings.…”

Section: Discussionsupporting

confidence: 92%

Growth arrest-specific gene 6 expression in human breast cancer

et al. 2008

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Growth arrest-specific gene 6 (Gas6), identified in 1995, acts as the ligand to the Axl/Tyro3 family of tyrosine kinase receptors and exerts mitogenic activity when bound to these receptors. Overexpression of the Axl/Tyro3 receptor family has been found in breast, ovarian and lung tumours. Gas6 is upregulated 23-fold by progesterone acting through the progesterone receptor B (PRB). Recently, Gas6 has been shown to be a target for overexpression and amplification in breast cancer. Quantitative real-time PCR analysis was used to determine the levels of Gas6 mRNA expression in 49 primary breast carcinomas. Expression of PRB protein was evaluated immunohistochemically with a commercially available PRB antibody. The results showed a positive association between PRB protein and Gas6 mRNA levels (P ¼ 0.04). Gas6 correlated positively with a number of favourable prognostic variables including lymph node negativity (P ¼ 0.0002), younger age at diagnosis (P ¼ 0.04), smaller size of tumours (P ¼ 0.02), low Nottingham prognostic index scores (P ¼ 0.03) and low nuclear morphology (P ¼ 0.03). This study verifies for the first time the association between PRB and Gas6 in breast cancer tissue.

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Section: Discussionsupporting

confidence: 92%

Growth arrest-specific gene 6 expression in human breast cancer

et al. 2008

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“…Human BRCA-1 mutant breast cancers frequently exhibit p53 mutation (Gudmundsdottir and Ashworth, 2006), and p53 haploinsufficiency increases cancer incidence in mouse models. Brca1 loss in mice produces an exaggerated proliferative response to exogenous progesterone (Ma et al, 2006) and mifepristone is cancer protective (Poole et al, 2006). Finally, Brca1-deficient mammary glands demonstrate increased ANG1 (Furuta et al, 2006), Igf-1, Irs-1 and Igf-1r (Shukla et al, 2006), indicating that multiple pathways implicated in breast carcinogenesis are altered by Brca1 loss.…”

Section: Introductionmentioning

confidence: 97%

Activation of estrogen signaling pathways collaborates with loss of Brca1 to promote development of ERα-negative and ERα-positive mammary preneoplasia and cancer

et al. 2007

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BRCA1 can regulate estrogen receptor-a (ERa) activity. This study tested the hypotheses that Brca1 loss in mammary epithelium alters the estrogenic growth response and that exposure to increased estrogen or ERa collaborates with Brca1 deficiency to accelerate preneoplasia and cancer development. Longer ductal extension was found in mammary glands of Brca1 f/f;MMTV-Cre mice during puberty as compared to wild-type mice. Terminal end bud differentiation was impaired in Brca1 mutant mice with preservation of prolactin-induced alveolar differentiation. Exogenous estrogen stimulated an abnormal sustained increase in mammary epithelial cell proliferation and the appearance of ERa-negative preneoplasia in postpubertal Brca1 mutant mice. Carcinogenesis was investigated using Brca1 f/f;MMTV-Cre mice hemizygous for p53. Exogenous estrogen increased the percentage of mice with multiple hyperplastic alveolar nodules. Targeted conditional ERa overexpression in mammary epithelial cells of mice that were Brca1 mutant and hemizygous for p53 increased the percentage of mice exhibiting multiple hyperplastic nodules, invasive mammary cancers and cancer multiplicity. Significantly more than half of the preneoplasia and cancers were ERa negative even as their initiation was promoted by ERa overexpression.

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“…Recently, however, BRCA1 has been shown to interact with and regulate estrogen receptor ␣ (ER␣) and progesterone receptor (PR) transcriptional activation (15)(16)(17). Of the Ͼ50 proteins known to interact with BRCA1, only ER␣ and PR have expression profiles similar to BRCA1 mutationassociated tumors.…”

mentioning

confidence: 99%

Estrogen receptor α is a putative substrate for the BRCA1 ubiquitin ligase

Eakin¹,

MacCoss

Finney

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

163

155

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The breast cancer suppressor protein, BRCA1, is a ubiquitin ligase expressed in a wide range of tissues. However, inheritance of a single BRCA1 mutation significantly increases a woman's lifetime chance of developing tissue-specific cancers in the breast and ovaries. Recently, studies have suggested this tissue specificity may be linked to inhibition of estrogen receptor ␣ (ER␣) transcriptional activation by BRCA1. Here, we show that ER␣ is a putative substrate for the BRCA1/BARD1 ubiquitin ligase, suggesting a possible mechanism for regulation of ER␣ activity by BRCA1. Our results show ER␣ is predominantly monoubiquitinated in a reaction that involves interactions with both BRCA1 and BARD1. The regions of BRCA1/BARD1 necessary for ER␣ ubiquitination include the RING domains and at least 241 and 170 residues of BRCA1 and BARD1, respectively. Cancer-predisposing mutations in BRCA1 are observed to abrogate ER␣ ubiquitination. The identification of ER␣ as a putative BRCA1/BARD1 ubiquitination substrate reveals a potential link between the loss of BRCA1/BARD1 ligase activity and tissue-specific carcinoma.breast cancer ͉ ubiquitylation ͉ ubiquitination ͉ steroid hormone receptor T he breast cancer suppressor protein, BRCA1, is essential for early development and associated with a number of cellular processes including cell proliferation, cell cycle progression, apoptosis, and DNA repair/recombination. Inheritance of a single mutation in BRCA1 increases a woman's lifetime risk of developing breast cancer from 1 in 9 to greater than 1 in 2 (1). Additionally, in sporadic nonfamilial cases of breast cancer, BRCA1 expression is significantly reduced, indicating loss of BRCA1 at the protein or mRNA level (2, 3). Therefore, BRCA1 inactivation either through mutation or repression of gene expression is implicated in all forms of breast cancer development.The only known enzymatic activity associated with BRCA1 is its activity as a ubiquitin protein ligase (4). Attachment of ubiquitin to substrates is a versatile method of regulation involved in practically all aspects of cell biology. Substrate ubiquitination involves several steps and a well-known trio of enzymes called ubiquitin activating (E1), ubiquitin conjugating (E2), and ubiquitin ligase (E3). The E3 activity of BRCA1 has been localized to the N-terminal RING domain and depends on heterodimerization with the RING domain of BARD1 (5). Importantly, all BRCA1 cancer-predisposing mutations within the RING domain are observed to eliminate the BRCA1/ BARD1 E3 activity both in vitro and in vivo (5-7). This strongly suggests a link between the tumor suppressor function of BRCA1 and its E3 activity. The ultimate fate of a ubiquitinated substrate depends on both the number of ubiquitins linked in a chain and the ubiquitin chain topology (8). BRCA1/BARD1 has been observed to monoubiquitinate proteins as well as build Lys-6-linked polyubiquitin chains. Lys-6-linked chains are recognized by the 26S proteasome for deubiquitination rather than degradation (9), suggesting ubiquitinat...

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The Breast Cancer Susceptibility Gene BRCA1 Regulates Progesterone Receptor Signaling in Mammary Epithelial Cells

Cited by 111 publications

References 59 publications

Growth arrest-specific gene 6 expression in human breast cancer

Growth arrest-specific gene 6 expression in human breast cancer

Activation of estrogen signaling pathways collaborates with loss of Brca1 to promote development of ERα-negative and ERα-positive mammary preneoplasia and cancer

Estrogen receptor α is a putative substrate for the BRCA1 ubiquitin ligase

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