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      Progesterone Receptor Isoforms, PR-B and PR-A, in Breast Cancer: Correlations with Clinicopathologic Tumor Parameters and Expression of AP-1 Factors

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          Abstract

          In the present study, we used Western blot analysis to determine the expression of the progesterone receptor (PR) isoforms, PR-B and PR-A, in breast tumors (n = 53), and correlated the expression patterns of the two isoforms with the clinicopathological parameters of these tumors and with expression of the AP-1 family of transcription factors. Expression of the two PR isoforms correlated significantly with each other, indicating that the expression of the two isoforms is probably regulated in a correlated fashion. Expression of both isoforms correlated significantly with expression of the estrogen receptor (ER). Furthermore, expression of PR-B was found to correlate significantly with the absence of ErbB2/neu. For the AP-1 factors, Fra-1 expression showed an inverse correlation with PR-B expression. In contrast, expression of FosB correlated significantly with expression of both isoforms, and the association was stronger with PR-B expression. An analysis of the ratio of expression of the two isoforms showed that most of the tumors expressed PR-A levels which were equal or higher than the corresponding PR-B expression levels (together 94% of the analyzed tumors) indicating that, in mammary carcinomas, a predominance of the PR-A isoform over the PR-B isoform seems to be the case. While there was no statistically significant correlation with age, staging and histological type, expression of both isoforms correlated with a more differentiated phenotype (G1/G2 grading). However, this association was stronger for PR-B. Also, a PR-A ≤ PR-B expression level was associated with G1/G2 grading, while a PR-A > PR-B expression level showed an association with a more undifferentiated phenotype (G3 grading). The expression level of the two PR isoforms might prove to be of prognostic and/or predictive value, especially since the two isoforms have been shown to be functionally different and to modulate the response of tumor cells to progestins and antiprogestins differently.

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          Most cited references 4

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          Expression pattern of the AP-1 family in breast cancer: association of fosB expression with a well-differentiated, receptor-positive tumor phenotype.

          In the present study, the expression of members of the AP-1 family of transcription factors in breast tumors (n = 53) was investigated by Western blot with antibodies specific for each of the AP-1 family members (c-jun, junB, junD and c-fos, fosB, fra1 and fra2). The tumors were characterized with regard to grading, staging, histology, steroid-receptor-expression status and c-erbB2/neu expression. For comparison, normal breast-tissue samples, human breast-cancer cell lines (T47D and MDA-MB231) and the transformed human breast epithelial cell line HBL100 were also analyzed. For c-jun, junB, c-fos and fra2, a relatively uniform expression pattern without significant differences among tumors was observed. junD-protein amounts varied strongly in the tumor specimens. fosB-expression levels also varied strongly in the tumors, weak/absent expression being found in 47%, while 45% exhibited strong/very strong levels of expression. While none of the other AP-1 family members showed significant correlations with clinico-pathological tumor parameters or receptor status, expression of fosB was found to correlate significantly with positive steroid-hormone-receptor status (in the tumors and the cell lines) and a more differentiated tumor phenotype. Expression of 2 fra-1-specific bands of 33 and 36.5 kDa showed significant negative correlation with fosB expression, as well as with estrogen-receptor status and differentiation. We conclude that strong differences in the expression pattern of AP-1 family members are present in breast tumors, and that certain members of this family, such as fosB and fra-1, might be involved in the pathogenesis of these tumors. Copyright 1999 Wiley-Liss, Inc.
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            The N-terminal region of the chicken progesterone receptor specifies target gene activation.

            Steroid hormone receptors belong to a family of nuclear receptors that trigger transcriptional activation of target genes by specific binding to DNA recognition sequences, usually located in the 5'-flanking region of the target gene. Nuclear receptors appear to be segmented proteins and extensive structure-function analyses have attempted to elucidate the functional significance of individual segments. Two of these regions have been defined as the domains responsible for recognition of responsive elements of target genes (region C) and hormone binding (region E) (refs 2-7). But the functional significance of the N-terminal region (A/B), which diverges extensively even for a given receptor between different species, has remained obscure. We have previously cloned, expressed and analysed the chicken progesterone receptor (cPR) (ref. 8). This receptor and its human homologue from T47D breast cancer cells are unique among the steroid hormone receptors in that two forms, A and B, are present in equal amounts in cytosolic extracts, the latter having the higher molecular weight. For the chicken progesterone receptor, we have presented evidence suggesting that the cPR form A corresponds to an N-terminally truncated form of B (ref. 8). Here we report on the functional difference between the forms A and B in the transcriptional activation of two target genes.
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              The molecular biology of RU486. Is there a role for antiprogestins in the treatment of breast cancer?

               K B Horwitz (1992)
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                Author and article information

                Journal
                HRE
                Horm Res Paediatr
                10.1159/issn.1663-2818
                Hormone Research in Paediatrics
                S. Karger AG
                1663-2818
                1663-2826
                2000
                2000
                15 February 2001
                : 54
                : 1
                : 32-37
                Affiliations
                aInstitute of Pathology, Department of Gynecopathology, University Hospital Eppendorf, Hamburg, and bInstitute for Hormone and Fertility Research, University of Hamburg, Germany
                Article
                63434 Horm Res 2000;54:32–37
                10.1159/000063434
                11182633
                © 2001 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 1, Tables: 2, References: 23, Pages: 6
                Categories
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