Progesterone Receptor Nonclassical Transcriptional Mechanisms in Breast Cancer.

PATRICIA V. ELIZALDE

Salt Beach, Kingscliff NSW

Congreso; 5Th PacRim Breast and prostate Cancer Meeting; 2011

PacRim Prostate and Breast Cancer Group

  Experimental and clinical evidence points to a critical role of progesterone and the nuclear progesterone receptor (PR) in controlling mammary gland tumorigenesis. However, the molecular mechanisms of progesterone action in breast cancer still remain elusive. 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, members of the activator protein 1 (AP-1) TF, via p42/p44 MAPKs. AP-1 activation leads to the assembly of a multi-component complex at the proximal cyclin D1 promoter, functioning as an enhanceosome, 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 also explored the clinical significance of PR and AP-1 nuclear interaction in breast tumors. Unexpectedly, nuclear co-localization of PR and phospho c-Jun was a marker of good prognosis and better overall survival in patients treated with tamoxifen (TAM), an anti-ER therapy. Rationale for these clinical findings was provided by our demonstration that TAM inhibited progestin-induced AP-1 transcriptional activation in breast cancer sensitive to its antiproliferative effects. 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.