Heregulin induces breast cancer growth by upregulating p21CIP1 and Bcl-XL expression via assembly of a PR/Stat3 transcriptional complex.

PROIETTI, CECILIA J.; IZZO, FRANCO; MERCOGLIANO, FLORENCIA; DE MARTINO, MARA; GALIGNIANA, NATALIA M.; CORDO RUSSO, ROSALÍA; VENTURUTTI, LEANDRO; SCHILACI, ROXANA; ELIZALDE, PATRICIA V.

San Francisco

Congreso; ENDO Annual Meeting 2014; 2014

Endocrine Society

Progesterone receptor (PR), signal transducer and activator of transcription 3 (Stat3) and the ErbB family of receptor tyrosine kinases (RTKs), are major players in the breast cancer scenario. We have previously demonstrated that heregulin (HRG), a ligand of RTKs, transactivates PR both in C4HD cells, from a murine progestin-dependent mammary tumor, and in the human breast cancer cell line T47D (1). We have also shown that HRG activates Stat3 by a mechanism that requires PR signaling and that this event drives breast cancer growth (2). In this work, we studied whether HRG induces PR and Stat3 interaction in the progesterone response elements (PREs) in the promoters of two endogenous genes involved in cell cycle regulation and modulated by progesterone: bcl-X and p21CIP1. By performing chromatin immunoprecipitation assays, we found that HRG induces the assembly of Stat3 and PR as a transcriptional complex in the transcription of bcl-X and p21CIP1. Notably, this complex drives in vitro and in vivo HRG-induced breast cancer growth. In addition, we found that both the cytoplasmic and nuclear functions of Stat3 are required for HRG stimulation of p21CIP1 and Bcl-XL expression and for HRG-induced proliferation of breast cancer cells, as demonstrated both by in vitro [3H]-thymidine incorporation assays and by preclinical studies in mice. We also explored the clinical significance of PR and Stat3 nuclear coexpression in breast tumors through a retrospective study in a cohort of 125 PR+ primary invasive breast carcinomas. Immunofluorescence and confocal microscopy analyses revealed that PR and Stat3 nuclear coexpression correlated with better overall survival (OS), both in the total cohort (p=0.007) and in the subgroup of patients treated with the selective estrogen receptor modulator tamoxifen (TAM) (n=115) (p=0.043). Our findings demonstrate that HRG induces the assembly of a transcriptional complex between PR and Stat3 which binds the PREs in bcl-X and p21CIP1 promoters and drives breast cancer cell growth. In addition, nuclear coexpression of PR and Stat3 was demonstrated to correlate with better OS suggesting the presence of the complex PR/Stat3 as a potential predictor of benefit from TAM therapy in breast cancer patients.