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

DÍAZ FLAQUÉ C MARÍA; NATALIA M GALIGNIANA; WENDY BÉGUELIN; ROCIO VICARIO; CECILIA J PROIETTI; ROSALIA CORDO RUSSO; MARTIN A RIVAS; MERCEDES TKACH; PABLO GUZMAN; JUAN C ROA; ESTEBAN MARONNA; VIVIANA PINEDA; SERGIO MUÑOZ; FLORENCIA MERCOGLIANO; EDUARDO CHARREAU; PATRICIO YANKILEVICH; ROXANA SCHILLACI; PATRICIA V ELIZALDE

BREAST CANCER RESEARCH

BIOMED CENTRAL LTD

Lugar: Londres; Año: 2013

1465-5411

AbstractIntroductionThe role of the progesterone receptor (PR) in breast cancer remains a major clinicalchallenge. Although PR induces mammary tumor growth, its presence in breast tumors is amarker of good prognosis. We investigated coordinated PR rapid and nonclassicaltranscriptional effects governing breast cancer growth and endocrine therapy resistance.MethodsWe used breast cancer cell lines expressing wild-type and mutant PRs, cells sensitive andresistant to endocrine therapy, a variety of molecular and cellular biology approaches, in vitroproliferation studies and preclinical models to explore PR regulation of cyclin D1 expression,tumor growth, and response to endocrine therapy. We investigated the clinical significance ofactivator protein 1 (AP-1) and PR interaction in a cohort of 99 PR-positive breast tumors byan immunofluorescence protocol we developed. The prognostic value of AP-1/PR nuclearcolocalization in overall survival (OS) was evaluated using Kaplan-Meier method, and Coxmodel 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 andtranscriptional effects, progestin induces the assembly of a transcriptional complex amongAP-1, Stat3, PR, and ErbB-2 which functions as an enhanceosome to drive breast cancergrowth. Our studies in a cohort of human breast tumors identified PR and AP-1 nuclearinteraction 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 ourdemonstration that Tam inhibits rapid and genomic PR effects, rendering breast cancer cellssensitive to its antiproliferative effects.ConclusionsWe here provided novel insight into the paradox of PR action as well as new tools to identifythe subgroup of ER+/PR + patients unlikely to respond to ER-targeted therapies.