Pten loss promotes MAPK pathway dependency in HER2/neu breast carcinomas

Significance PTEN mutations are associated with disease progression and therapy resistance in human epidermal growth factor receptor 2 (HER2/neu)-amplified breast cancer patients but the role of PTEN loss in breast cancer maintenance is unknown. Here, using a regulatable RNAi mouse model of HER2/neu-driven metastatic breast cancer, we show that Pten silencing accelerates disease progression and that restoration of endogenous Pten expression triggers marked disease regression. By comparing and contrasting how pharmacologic perturbations of various signaling pathways compare to genetic reactivation of Pten, we identify a requirement for Mek signaling in Pten-suppressed tumors. Our findings imply that even advanced tumors can remain dependent on Pten loss and provide a rationale for exploring the utility of MEK inhibitors in therapy-resistant breast cancer patients acquiring PTEN mutations. Loss of the tumor suppressor gene PTEN is implicated in breast cancer progression and resistance to targeted therapies, and is thought to promote tumorigenesis by activating PI3K signaling. In a transgenic model of breast cancer, Pten suppression using a tetracycline-regulatable short hairpin (sh)RNA cooperates with human epidermal growth factor receptor 2 (HER2/neu), leading to aggressive and metastatic disease with elevated signaling through PI3K and, surprisingly, the mitogen-activated protein kinase (MAPK) pathway. Restoring Pten function is sufficient to down-regulate both PI3K and MAPK signaling and triggers dramatic tumor regression. Pharmacologic inhibition of MAPK signaling produces similar effects to Pten restoration, suggesting that the MAPK pathway contributes to the maintenance of advanced breast cancers harboring Pten loss.

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