Germ‐line mutations in <i>BRCA1</i> or <i>BRCA2</i> in the normal breast are associated with altered expression of estrogen‐responsive proteins and the predominance of progesterone receptor A

Mote, Patricia A.; Leary, Jennifer; Avery, Kelly A; Sandelin, Kerstin; Chenevix-Trench, Georgia; Kirk, Judy; Clarke, Christine L.; Investigators, kConFab

doi:10.1002/gcc.10321

Cited by 87 publications

(52 citation statements)

References 51 publications

(62 reference statements)

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“…biological phenotype associated with heterozygous mutations in the BRCA1 and BRCA2 genes, and complements the recent reports of an effect on PgR expression by Mote et al (2004). The delayed PgR response to E 2 in the mutation carriers is paradoxical in the face of the in vitro evidence suggesting that the BRCA1 gene product is a repressor of both nuclear and nongenomic mechanisms of ERa action (Fan et al, 1999(Fan et al, , 2001Razandi et al, 2004).…”

Section: Discussionsupporting

confidence: 79%

“…One way of confirming this would be to use more specific antibodies to determine the ratios of the two PgR isoforms in the breast epithelium from the mutation carriers compared to those from subjects at population risk of breast cancer. This approach has been used by Mote et al (2004) who have shown that not only is the ratio of PgRA to PgRB altered in favour of PgRA in normal breast tissue taken from BRCA1 and BRCA2 mutation carriers but also that expression of both isoforms is markedly reduced compared to tissue from normal-risk women. This suggests that the reduced levels of PgR expression seen in the mutation carriers in the present study is due to a reduction in both PgR isoforms.…”

Section: Discussionmentioning

confidence: 99%

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Effects of oestrogens and anti-oestrogens on normal breast tissue from women bearing BRCA1 and BRCA2 mutations

Bramley¹,

Clarke²,

Howell

et al. 2006

Br J Cancer

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There is considerable interest in whether anti-oestrogens can be used to prevent breast cancer in women bearing mutations in the BRCA1 and BRCA2 genes. The effects of oestradiol (E 2 ), tamoxifen (TAM) and fulvestrant (FUL) on proliferation and steroid receptor expression were assessed in normal breast epithelium taken from women at varying risks of breast cancer and implanted into athymic nude mice, which were treated with E 2 in the presence and absence of TAM or FUL. Tissue samples were taken at various time points thereafter for assessment of proliferative activity and expression of oestrogen and progesterone receptors (ERa and PgR) by immunohistochemistry. Oestradiol increased proliferation in the breast epithelium from women carrying mutations in the BRCA1/2 genes, those otherwise at increased risk and those at population risk of breast cancer. This increase was reduced by both TAM and FUL in all risk groups. In the absence of E 2 , PgR expression was reduced in all risk groups but significantly more so in the BRCAmutated groups. Subsequent E 2 treatment caused a rapid, complete induction of PgR expression in the population-risk group but not in the high-risk or BRCA-mutated groups in which PgR induction was significantly delayed. These data suggest that the mechanisms by which E 2 induces breast epithelial PgR expression are impaired in BRCA1/2 mutation carriers, whereas those regulating proliferation remain intact. We conclude that early anti-oestrogen treatment should prevent breast cancer in very high-risk women. British Journal of Cancer (2006) Approximately 5% of all cases of breast cancer are associated with inherited predisposition syndromes and about half of these are attributable to mutations in the BRCA1 and BRCA2 genes (Hopper, 2001). Carriers of mutations in the BRCA1 and BRCA2 genes have up to a 90% lifetime risk of developing breast cancer (Rebbeck, 2002) and effective preventative strategies are required for these women.A number of trials have now shown that endocrine agents such as tamoxifen (TAM) or raloxifene can prevent breast cancer in women at increased risk of the disease (Cuzick et al, 2003). The question arises as to whether agents such as these can be used for prevention specifically in women bearing BRCA1 or BRCA2 mutations. The prevalence of mutations in the total cohort in the NSABP P1 trial was unknown (Fisher et al, 1998) and therefore no conclusion regarding the effectiveness of TAM in mutation carriers can be made from this study. It has been suggested that endocrine agents such as TAM will not be effective in preventing breast cancer in BRCA1 mutation carriers because the majority of tumours (up to 80%) arising in these women are oestrogen receptor a (ERa) negative, have a high mitotic rate and are of high histological grade (Lakhani, 1999;Lakhani et al, 2002). All these features are associated with resistance to endocrine therapy and it is clear from the overview that TAM and raloxifene reduce the incidence of ERa-positive but not -negative tumours (Cuzick et al, 2003). ...

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Effects of oestrogens and anti-oestrogens on normal breast tissue from women bearing BRCA1 and BRCA2 mutations

Bramley¹,

Clarke²,

Howell

et al. 2006

Br J Cancer

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“…In humans, loss of function of one BRCA1 allele has been associated with a relative increase in PR A levels, alterations in ERa-regulated gene expression, but a normal ERa expression pattern (Mote et al, 2004). Similarly, in the study reported here, a normal pattern of nuclear-localized ERa expression was found in the normal-appearing mammary ductal cells.…”

Section: Discussionsupporting

confidence: 74%

Promotion of mammary cancer development by tamoxifen in a mouse model of Brca1-mutation-related breast cancer

Jones

Halama

et al. 2005

Oncogene

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Loss of full-length Brca1 in mammary epithelial cells of the mouse mammary tumor virus (MMTV)-Cre Brca1 conditional exon 11 deletion mouse model results in the development of mammary adenocarcinomas with similar genetic changes to those found in human BRCA1-mutation-related breast cancers. We used this experimental model to evaluate the chemopreventive effect of tamoxifen on the development of mammary preneoplasia and adenocarcinoma. No protective effects of tamoxifen administration on mammary cancer development were found. Instead, tamoxifen treatment significantly increased rates of mammary epithelial cell proliferation and the prevalence of mammary hyperplasia at 6 months of age. Tamoxifen-exposed mice developed adenocarcinomas at younger ages than control mice and a higher percentage of mice developed adenocarcinomas by 12 months of age. Both whole mouse and tissue culture cell models were used to test if loss of full-length Brca1 was associated with a relative increase in the agonist activity of tamoxifen. Tamoxifen induced increased ductal growth in MMTV-Cre Brca1 conditional mice compared to wild type. Estrogen receptor alpha (ERa) expression was downregulated in the tamoxifen-induced hyperplasias. Reducing BRCA1 levels in MCF-7 cells using siRNA resulted in a relative increase in the agonist activity of tamoxifen. Results suggest a model of mammary cancer progression in which loss of full-length Brca1 altered the agonist/antagonist activity of tamoxifen, resulting in tamoxifen-induced mammary epithelial cell proliferation with subsequent loss of ERa expression and development of ERa-negative hyperplasias and adenocarcinomas.

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“…In vitro studies indicate that PgR-A exerts modulating effects on cell morphology and adhesion (McGowan et al 1999;Grahal et al 2005). In the normal tissue of BRCA mutation carriers, PgR-B is absent (Mote et al 2004). …”

Section: Progesterone Receptors (Pgr)mentioning

confidence: 99%

Intraepithelial Neoplasia of Breast

Monti¹,

Castillo²

2012

Intraepithelial Neoplasia

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Germ‐line mutations in BRCA1 or BRCA2 in the normal breast are associated with altered expression of estrogen‐responsive proteins and the predominance of progesterone receptor A

Cited by 87 publications

References 51 publications

Effects of oestrogens and anti-oestrogens on normal breast tissue from women bearing BRCA1 and BRCA2 mutations

Effects of oestrogens and anti-oestrogens on normal breast tissue from women bearing BRCA1 and BRCA2 mutations

Promotion of mammary cancer development by tamoxifen in a mouse model of Brca1-mutation-related breast cancer

Intraepithelial Neoplasia of Breast

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