Heregulin Co-opts PR transcriptional action via Stat3 role as a coregulator to drive cancer growth

Accumulated findings have demonstrated the presence of bidirectional interactions betweenprogesterone receptor (PR) and the ErbB family of receptor tyrosine kinases signaling pathways inbreast cancer. We previously revealed signal transducer and activator of transcription 3 (Stat3) asa nodal convergence point between said signaling pathways proving that Stat3 is activated by oneof the ErbBs? ligands, heregulin (HRG)1 via ErbB2 and through the co-option of PR as a signalingmolecule. Here, we found that HRG1 induced Stat3 recruitment to the promoters of the progestin-regulatedcell cycle modulators Bcl-XL and p21CIP1 and also stimulated Stat3 binding to themouse mammary tumor virus promoter, which carries consensus progesterone response elements.Interestingly, HRG1-activated Stat3 displayed differential functions on PR activity depending onthe promoter bound. Indeed, Stat3 was required for PR binding in bcl-X, p21CIP1, and c-mycpromoters while exerting a PR coactivator function on the mouse mammary tumor virus promoter.Stat3 also proved to be necessary for HRG1-induced in vivo tumor growth. Our resultsendow Stat3 a novel function as a coregulator of HRG1-activated PR to promote breast cancergrowth. These findings underscore the importance of understanding the complex interactionsbetween PR and other regulatory factors, such as Stat3, that contribute to determine the contextdependenttranscriptional actions of PR. (MoFil: Proietti Anastasi, Cecilia Jazmín. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Izzo, Franco. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Díaz Flaqué, María Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Cordo Russo, Rosalia Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Venturutti, Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: de Martino, Mara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Pineda, Viviana. Universidad de la Frontera. Departamento de Anatomía Patológica; ChileFil: Muñoz, Sergio. Universidad de la Frontera. Departamento de Anatomía Patológica; ChileFil: Guzman, Pablo. Universidad de la Frontera. Departamento de Anatomía Patológica; ChileFil: Roa, Juan C.. Universidad de la Frontera. Departamento de Anatomía Patológica; Chile. Pontificia Universidad Católica de Chile. Departamento de Anatomía Patológica; Chile. Pontificia Universidad Católica de Chile. Advanced Center for Chronic Diseases; ChileFil: Schillaci, Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Elizalde, Patricia Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentin