Sp1 Binding Sites and An Estrogen Response Element Half-Site Are Involved in Regulation of the Human Progesterone Receptor A Promoter

Petz, Larry N.; Nardulli, Ann M.

doi:10.1210/mend.14.7.0493

Cited by 140 publications

(104 citation statements)

References 59 publications

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“…It has been demonstrated that this half-ERE/Sp1 binding site is protected to a greater extent when MCF-7 cells are treated with estrogen, suggesting that this region may be involved in estrogen-regulated gene expression. 28) These results also suggest that, in human breast cancer, PRA may be more closely regulated by estrogen through ERα than PRB. Both PRA and B promoters have been reported to be regulated by estrogen, but there may be different pathways, or responsiveness to estrogen actions.…”

Section: Discussionmentioning

confidence: 69%

Progesterone Receptor A and B Isoforms in the Human Breast and Its Disorders

Ariga¹,

Suzuki²,

Moriya³

et al. 2001

Japanese Journal of Cancer Research

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Human progesterone receptor (PR) exists as two isoforms, A and B. These isoforms are encoded by separate mRNAs which are transcribed from two distinct promoters, both of which are under estrogen control.1, 2) PRA and PRB are both expressed in progesterone target tissues at comparable levels. The ratio of PRA:PRB has been suggested to influence the biological actions of progesterone. Therefore, investigating the relative ratio of PR isoforms in progesterone-responsive tissues may provide important insights into the physiology and perhaps pathogenesis relating to progesterone-mediated actions.In human breast cancer cells, PRA over-expression has been reported to be associated with an alteration in adhesive properties.3) Previous studies using immunoblot analysis have demonstrated very high levels of PRA (up to 100 fold higher than PRB) in a subset of human breast tumors.4) However, immunolocalization of PR isoform proteins has not been reported in detail in human breast cancer. Therefore, in this study, we first immunolocalized PRA and PRB in human breast cancer and intraductal epithelial proliferative lesions. We then examined the mRNAs for PRA and PRB in invasive ductal carcinoma cases using reverse transcription-polymerase chain reaction (RT-PCR) analysis. We also examined the correlation between these findings and clinicopathological factors of invasive ductal carcinoma including estrogen receptor (ER) α status, Ki67 labeling index (LI), histological grades, and lymph node status, in order to further characterize the biological significance of these PR isoforms in breast carcinoma. MATERIALS AND METHODSCases Surgical pathology specimens were retrieved from the pathology files of Tohoku University Hospital, Sendai, Kawasaki University Hospital, Kurashiki, and Tohoku Kosai Hospital, Sendai. These specimens included 47 cases of invasive ductal carcinoma (IDC), 40 cases of ductal carcinoma in situ (DCIS), 27 cases of atypical ductal hyperplasia (ADH), and 27 cases of proliferative disease without atypia (PDWA) including moderate and florid hyperplasia of the usual type. Pathological diagnosis was based on the work of Dupont et al. 5) and of Ottesen et al. 6)Classification of DCIS was based on the Consensus Conference on the Classification of Ductal Carcinoma In Situ in 1997. 7) Non-pathological breast tissues were available for examination in 13, 12 and 12 cases of DCIS, ADH and PDWA, respectively. All of these specimens were fixed in

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Section: Discussionmentioning

confidence: 69%

Progesterone Receptor A and B Isoforms in the Human Breast and Its Disorders

Ariga¹,

Suzuki²,

Moriya³

et al. 2001

Japanese Journal of Cancer Research

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“…This receptor is one of the most intensely studied estrogen-regulated genes and is widely recognized as a marker of estrogen activity [32]. Clusters of estrogen response element (ERE) half-sites, which are essential for transactivation of the PR gene by liganded response elements, are present within the PR gene promoter [33][34][35]. Almost all hormone treatment protocols designed to elicit effects of progesterone involve preparatory estrogen priming to induce PR [36,37].…”

Section: Discussionmentioning

confidence: 99%

Uterotrophic effects of cow milk in immature ovariectomized Sprague–Dawley rats

Zhou

Qin

et al. 2009

Environ Health Prev Med

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Objectives Milk contains considerable quantities of estrogens and progesterone and as such may be one of the risk factors for hormone-related cancers. To determine the hormonal effects of commercial and traditional types of milk, we performed uterotrophic tests. Methods Forty-five rats were ovariectomized and divided into three groups of 15 animals each. The animals were kept for 7 days on powdered chow and one of three different liquids: commercial milk (C), traditional milk (T), or water. At autopsy, wet and dry uterine weights were determined. The cell heights of the uterine epithelium and endometrium were determined. The uterine 5-bromo-2-deoxyuridine (BrdU) labeling index of the epithelium and endometrium gland epithelium was also assessed. Results The weights of wet and dry uterus were 142 ± 13 and 112 ± 10 mg in the C group, 114 ± 30 and 91 ± 24 mg in the T group, and 87 ± 6 and 69 ± 5 mg in the W group. Significant differences in wet and dry uterus weights were found between all pairs of groups. The ratio of the wet uterine weight to body weight was significantly higher in the C and T groups than in the W group. The heights of the uterine epithelium and endometrium were higher and BrdU labeling index was greater in the C group than in the T and W groups. Conclusions Commercially available milk and traditional milk have uterotrophic effects on young ovariectomized rats. Our findings indicate that these uterotrophic effects in the milk groups were partly due to the estrogen and progesterone in the milk.

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“…However, some of these experiments used reporter constructs containing a consensus oestrogen response element (ERE) from the vitellogenin gene to examine the effects of the BRCA1 protein on ERa transcriptional activity (Fan et al, 1999), whereas others have shown that overexpression of BRCA1 abrogates the effects of E 2 on expression of the oestrogen-induced genes, pS2 and cathepsin D (Fan et al, 2001). The PgR gene promoter does not contain a complete ERE but it does have ERE half sites adjacent to those for Sp-1 (Petz and Nardulli, 2000), and it is possible that the BRCA1 protein has significantly different effects at this site in human breast epithelium in vivo. 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.…”

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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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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Sp1 Binding Sites and An Estrogen Response Element Half-Site Are Involved in Regulation of the Human Progesterone Receptor A Promoter

Cited by 140 publications

References 59 publications

Progesterone Receptor A and B Isoforms in the Human Breast and Its Disorders

Progesterone Receptor A and B Isoforms in the Human Breast and Its Disorders

Uterotrophic effects of cow milk in immature ovariectomized Sprague–Dawley rats

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

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