RNA sequence analysis of stable versus reversible EMT events and the resultant metastases

The ability of breast cancer cells to transiently transition between epithelial and mesenchymal states is critical to complete the metastatic process. In contrast, induction of epithelial-mesenchymal transition (EMT) through the acquisition of drug persistence is a more stable event. Herein, we utilize Her2 transformed human mammary epithelial (HMLE) cells to compare a reversible model of EMT induced by TGF-beta to a stable mesenchymal phenotype induced by chronic exposure to the ErbB kinase inhibitor, lapatinib. Indeed, only a TGF-beta cells capable of returning to an epithelial phenotype resulted in long bone metastasis (BM). These four cell populations were anylzed by RNA sequencing. Overall design: The Her2 transformed HMLE cells are referred to as the parental (Par) cell line and serves as the control. These cells were treated with TGF-beta every three days for a period of 4 weeks to induce EMT (TGFB). Alternatively, the parental cells were treated with 1 micromolar of lapatinib every three days also for 4 weeks and a proliferative drug resistant population (LAPR) emerged. The TGF-beta treated cells were engrafted onto the mammary fatpad and resultant long bone metasases (BM) were isolated and subcluted ex-vivo.

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Shinde A, Hardy SD, Kim D, Akhand SS, Jolly MK, Wang WH, Anderson JC, Khodadadi RB, Brown WS, George JT, Liu S, Wan J, Levine H, Willey CD, Krusemark CJ, Geahlen RL, Wendt MK