Cell density, Her2 and progesterone signaling regulate dissemination of breast cancer cells [miRNA-Seq]

Disseminated breast cancer cells display genotypes disparate from the predominant clone of the primary tumor before manifestation of metastasis, suggesting that cancer cell dissemination occurs preferentially early; however, the underlying molecular mechanisms are unknown. Investigating metastasis in a Her2-driven mouse model, we found that the progesterone-induced paracrine cytokines Wnt4 and Rankl induced migration and early dissemination shortly after Her2 activation. Once tumorigenic growth was established, progesterone receptor (PgR) expression was lost and Wnt4/Rankl induced proliferation. The altered response from migration to proliferation was determined by cell density involving miRNA-regulated PgR expression and was reversible. Cells from early, low-density lesions displayed more functional stemness traits than cells from dense, advanced tumors, migrated more and founded significantly more metastases. The data suggest that many metastases are derived from early-disseminated cancer cells, implying that our concepts for systemic therapy need to be revised. We analysed miRNA expression in the Her2 expressing cell lines as well as the secreting miRNA containing particles to find out PgR regulating miRNAs