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

Abstract

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

Estrogen Receptor and Cytokeratin 5 Are Reliable Markers to Separate Usual Ductal Hyperplasia From Atypical Ductal Hyperplasia and Low-Grade Ductal Carcinoma In Situ

“…Previous studies have shown that PR expression tends to be higher in ADH and low-grade DCIS than in UDH. 10,19 Our results show a similar trend; however, these results must be interpreted with caution, because some ADH cases can be negative for PR and some UDH cases can be diffusely positive for PR staining.…”

“…Bcl-2 was chosen because of its expression in columnar cell lesions, and PR was chosen because previous studies have shown that PR tends to have higher expression in ADH and low-grade DCIS than UDH. 10,19 …”

Progestin-Dependent Induction of Vascular Endothelial Growth Factor in Human Breast Cancer Cells

“…3 This suggests that VEGF is regulated by progesterone in a cell type-specific manner and that progesterone-dependent VEGF expression may be widespread in breast cancer cell lines. Because expression of PR isoforms is dysregulated in human breast tumors, leading to excess in one PR isoform (11)(12)(13)22), we explored the PR isoform specificity of PR-dependent VEGF expression in progestin-stimulated breast tumor cells expressing individual PR isoforms. Our results presented in this communication identify PRB as the dominant PR isoform controlling VEGF induction in response to natural and synthetic progestins and also provide evidence that predominant presence of PRB in breast cancer cells permit ER to induce VEGF in breast cancer cells.…”

“…PRA and PRB are expressed in nearly equimolar amounts in normal breast, but synthesis of PRA and/or PRB tends to be dysregulated in breast cancer cells, such that the two isoforms are differentially expressed (11)(12)(13). Previous studies provide evidence that the majority of advanced-stage tumors are rich in PRA; however, PRB is the predominant isoform in ductal carcinoma in situ (13). Importantly, a ϩ331 G/A polymorphism in the PR gene was recently linked to increased expression of PRB in breast cells and increased risk of breast cancer (14).…”

Biological Roles of Estrogen and Progesterone in Human Endometrial Carcinoma - New developments in potential endocrine therapy for endometrial cancer -

“…In breast carcinoma, a significant proportion of tumors expressed very low levels of PRB and consequently exhibited a high PRA/PRB ratio [49]. PRA predominated in invasive ductal carcinoma [50]. In addition, breast carcinoma patients with PRA-rich tumors were generally associated with poorer disease-free survival rates or adverse clinical outcomes [51].…”