Responsiveness to Tamoxifen is associated with the assembly of an AP-1/Stat3/ErbB-2 non classical PR Transcriptional Complex in breast cancer patients

DÍAZ FLAQUÉ, CELESTE; NATALIA GALIGNIANA; ROSALIA CORDO RUSSO; CECILIA J. PROIETTI; FRANCO IZZO; MARÍA FLORENCIA MERCOGLIANO; LEANDRO VENTURUTTI; ROXANA SCHILLACI; ELIZALDE, PATRICIA V

San Francisco

Congreso; 95th Annual Meeting of the Endocrine Society; 2013

The molecular mechanisms through which the progesterone receptor (PR) controls breast cancer growth and response to endocrine treatments remain a major clinical challenge. PR acts as a transcription factor (TF) and as an activator of signaling pathways through a rapid or nongenomic mechanism. Furthermore, it participates in an extensive and bidirectional crosstalk with growth factors and estrogen receptor (ER) signaling. In the present work, we demonstrated that progestin treatment of breast cancer cells induces the rapid phosphorylation of c-Jun and c-Fos, (AP-1 TF), via p42/p44 MAPKs. AP-1 activation leads to the assembly at the proximal cyclin D1 promoter of a multi-component complex which functions as an enhaceosome, where AP-1 is loaded at its response element (TRE), PR is tethered to AP-1, the signal transducer and activator of transcription 3 (Stat3) is co-recruited to its binding sites located close to the TRE, and ErbB-2 is simultaneously loaded. This complex drives in vitro and in vivo progestin-induced breast cancer growth. We explored the clinical significance of PR and AP-1 nuclear interaction in breast tumors through a retrospective study in a cohort of 99 PR+ primary invasive breast carcinomas. Unexpectedly, evaluation of nuclear co-localization of PR and p-c-Jun by inmunofluorescence and confocal microscopy was a marker of good prognosis and better overall survival (OS) in patients treated with tamoxifen (TAM), an anti-ER therapy. We found that 81 tumors showed nuclear colocalization of both proteins and were significantly associated with the absence of nodal metastasis. Kaplan-Meier survival analysis revealed that colocalization correlated with better OS both in the total cohort and in the subgroup of patients that received TAM (n=85). A rationale for these clinical findings was provided by our demonstration that TAM inhibited progestin-induced AP-1 transcriptional activation in BT474-HR breast cancer cells which are sensitive to the antiproliferative effects of TAM. Our findings offer novel insight into the major clinical challenge of endocrine resistance, revealing that PR transcriptional complexes assembled via coordinated rapid and transcriptional PR actions govern breast cancer growth. These complexes are disrupted by TAM, rendering breast cancer cells sensitive to therapy.