Detection of progesterone receptor forms A and B by immunohistochemical analysis

Mote, Patricia A.

doi:10.1136/jcp.54.8.624

Cited by 104 publications

(78 citation statements)

References 45 publications

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“…These finding are consistent with previous studies indicating that overexpression of PR-A in PR-positive tumors may be associated with a more aggressive state. Although the ratios of PR-A and PR-B appear to be equivalent in the normal mammary gland, a subset of PR invasive tumors show an imbalance of PR-A and PR-B in favor of PR-A (Mote et al, 2001;Mote et al, 2002;Graham et al, 1995). MTA1 overexpression in human breast cancer cells also promotes an aggressive phenotype to the cells and induces tumorigenicity in nude mice (Mazumdar et al, 2001) (R.B.-Y.…”

Section: Discussionmentioning

confidence: 99%

Metastasis-associated protein 1 deregulation causes inappropriate mammary gland development and tumorigenesis

et al. 2004

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Emerging data suggest that metastasis-associated protein 1 (MTA1) represses ligand-dependent transactivation functions of estrogen receptor-alpha in cultured breast cancer cells and that MTA1 is upregulated in human breast tumors. However, the role of MTA1 in tumorigenesis in a physiologically relevant animal system remains unknown. To reveal the role of MTA1 in mammary gland development, transgenic mice expressing MTA1 under the control of the mouse mammary tumor virus promoter long terminal repeat were generated. Unexpectedly, we found that mammary glands of these virgin transgenic mice exhibited extensive side branching and precocious differentiation because of increased proliferation of ductal and alveolar epithelial cells. Mammary glands of virgin transgenic mice resemble those from wild-type mice in mid-pregnancy and inappropriately express β-casein, cyclin D1 andβ-catenin protein. Increased ductal growth was also observed in the glands of ovariectomized female mice, as well as of transgenic male mice. MTA1 dysregulation in mammary epithelium and cancer cells triggered downregulation of the progesterone receptor-B isoform and upregulation of the progesterone receptor-A isoform, resulting in an imbalance in the native ratio of progesterone receptor A and B isoforms. MTA1 transgene also increased the expression of progesterone receptor-A target genes Bcl-XL(Bcl2l1) and cyclin D1 in mammary gland of virgin mice, and,subsequently, produced a delayed involution. Remarkably, 30% of MTA1 transgenic females developed focal hyperplastic nodules, and about 7%exhibited mammary tumors within 18 months. These studies establish, for the first time, a potential role of MTA1 in mammary gland development and tumorigenesis. The underlying mechanism involves the upregulation of progesterone receptor A and its targets, Bcl-XL and cyclin D1.

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Section: Discussionmentioning

confidence: 99%

Metastasis-associated protein 1 deregulation causes inappropriate mammary gland development and tumorigenesis

et al. 2004

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“…Alternatively, the differences in expression of PgR in response to E 2 treatment may result from an alteration in the ratio of the A and B isoforms of the PR. Many commercially available antibodies used for PgR IHC fail to detect the B form of the receptor in formalin-fixed, paraffin-embedded tissues (Mote et al, 2001). The specificity of the antibody used in the present study is not known at present, but it is probable that it also does not detect PgRB in routinely processed tissue.…”

Section: Discussionmentioning

confidence: 76%

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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“…This is consistent with the expression of PRB in alveolar epithelial cells. Studies assessing their temporal and cell-specific expression patterns in the mammary gland are confusing due to the proportion of studies carried out before reagents capable of distinguishing the two isoforms became available (Mote et al 2001) as eluded to earlier. Some confusion has also arisen in terms of PR regulation in mouse and human, due to the more dispersed alveolar architecture of the virgin mouse gland.…”

Section: Progesterone As a Downstream Targetmentioning

confidence: 99%

“…It is important to note that PR is used as an indicator of intact estrogen action, and in all the studies mentioned hereafter the PR subtype has not been defined by the investigator. As discussed later, the specificity of the induction of PR subtypes can now be explored, as subtype-specific antibodies have been developed (Mote et al 2001). By 7 days of age, ERa has increased twofold in epithelial cells and is now located in both basal and luminal cells.…”

Section: Er Levels During Mammary Developmentmentioning

confidence: 99%

Pregnancy and the risk of breast cancer

Britt¹,

Ashworth²,

Smalley³

2007

Endocrine Related Cancer

198

175

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It is well established that childless women and women having children later in life are at an increased risk of developing breast cancer. In particular, women having a first child before 20 years of age have a 50% reduction in lifetime breast cancer risk when compared with women who do not have children. This protective effect is specific for estrogen receptor positive breast cancer. Nevertheless, it remains unclear how parity decreases breast cancer risk. Possible mechanisms of action include changes to the hormonal profile of parous women, a more differentiated and so less susceptible mammary gland or changes within specific epithelial cell subpopulations. In this review, we discuss the epidemiological evidence for the protective effects of parity on breast cancer. We also explore the mechanisms by which parity protects, with a particular emphasis on the role of stem cells and the interactions between stem cells and estrogen.

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Detection of progesterone receptor forms A and B by immunohistochemical analysis

Cited by 104 publications

References 45 publications

Metastasis-associated protein 1 deregulation causes inappropriate mammary gland development and tumorigenesis

Metastasis-associated protein 1 deregulation causes inappropriate mammary gland development and tumorigenesis

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

Pregnancy and the risk of breast cancer

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