Cell density, Her2 and progesterone signaling regulate dissemination of breast cancer cells [Gene expression]

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.