Progesterone receptor assembly of a transcriptional complex along with activator protein 1, signal transducer and activator of transcription 3 and ErbB-2 governs breast cancer growth and predicts response to endocrine therapy.

María C Díaz Flaqué,Natalia M Galigniana,Cecilia J Proietti,María Florencia Mercogliano,Rosalía Cordo Russo,Rocío Vicario,Patricio Yankilevich,Mercedes Tkach,Roxana Schillaci,Wendy Béguelin,Pablo Guzmán,Sergio Muñoz,Patricia V Elizalde,Viviana Pineda,Martín A Rivas,Eduardo H Charreau,Esteban Maronna,Juan C Roa

doi:10.1186/bcr3587

Abstract

IntroductionThe role of the progesterone receptor (PR) in breast cancer remains a major clinical challenge. Although PR induces mammary tumor growth, its presence in breast tumors is a marker of good prognosis. We investigated coordinated PR rapid and nonclassical transcriptional effects governing breast cancer growth and endocrine therapy resistance.MethodsWe used breast cancer cell lines expressing wild-type and mutant PRs, cells sensitive and resistant to endocrine therapy, a variety of molecular and cellular biology approaches, in vitro proliferation studies and preclinical models to explore PR regulation of cyclin D1 expression, tumor growth, and response to endocrine therapy. We investigated the clinical significance of activator protein 1 (AP-1) and PR interaction in a cohort of 99 PR-positive breast tumors by an immunofluorescence protocol we developed. The prognostic value of AP-1/PR nuclear colocalization in overall survival (OS) was evaluated using Kaplan-Meier method, and Cox model was used to explore said colocalization as an independent prognostic factor for OS.ResultsWe demonstrated that at the cyclin D1 promoter and through coordinated rapid and transcriptional effects, progestin induces the assembly of a transcriptional complex among AP-1, Stat3, PR, and ErbB-2 which functions as an enhanceosome to drive breast cancer growth. Our studies in a cohort of human breast tumors identified PR and AP-1 nuclear interaction as a marker of good prognosis and better OS in patients treated with tamoxifen (Tam), an anti-estrogen receptor therapy. Rationale for this finding was provided by our demonstration that Tam inhibits rapid and genomic PR effects, rendering breast cancer cells sensitive to its antiproliferative effects.ConclusionsWe here provided novel insight into the paradox of PR action as well as new tools to identify the subgroup of ER+/PR + patients unlikely to respond to ER-targeted therapies.

Highlights

The role of the progesterone receptor (PR) in breast cancer remains a major clinical challenge
MPA induces the rapid phosphorylation of c-Jun and c-Fos and activator protein 1 (AP-1) transcriptional activation via p42/p44 mitogen-activated protein kinases (MAPKs) We first explored the ability of the synthetic progestin medroxyprogesterone acetate (MPA) to phosphorylate c-Jun and c-Fos
MPA treatment of C4HD and T47D human breast cancer cells resulted in rapid phosphorylation of c-Jun and c-Fos, which was abolished by pre-incubation with the antiprogestin RU486 or by knockdown of PR expression with PR small interfering RNAs (Figure 1A, B and Additional file 1: Figure 1A)

Summary

Introduction

The role of the progesterone receptor (PR) in breast cancer remains a major clinical challenge. PR acts as a ligand-induced transcription factor (TF) interacting with specific progesterone response elements (PREs) in the promoter of target genes. Progestin regulates the expression of an important number of genes which lack canonical PREs in their promoters, including key regulators of cell cycle progression, such as cyclin D1, p21CIP1 and p27KIP1 [11,12,13]. This may occur via a nonclassical PR transcriptional mechanism through PR tethering to other TFs in the promoter of target genes. AP-1 involvement in breast cancer growth and expression of AP-1 members in human breast cancer have been reported [20,21,22]

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