signature=4c00066eaca5d0bdf2ba194e30337d46,19 Autophagy induction as a new therapy for HER2+ breast ...

摘要：

IntroductionHER2 is a receptor tyrosine kinase whose gene is amplified in ~20% human breast cancer patients. Allelic loss of the autophagy gene, beclin 1/BECN1, is associated with HER2 amplification in breast cancer; low beclin 1 mRNA expression is associated with increased risk of HER2-positive breast cancer; and overexpressed HER2 and Beclin 1 interact in cultured cells. However, the functional significance of HER2/Beclin 1 interaction and of altered autophagy in HER2-driven tumorigenesis and whether autophagy induction may be beneficial in preventing HER2-positive breast tumour growth is unknown.Material and methodsWe explored the regulation of autophagy in breast cancer cells by HER2 in vitro and the effects as well as genetic and pharmacological approaches to increase autophagy on HER2-driven breast cancer growth in vivo.Results and discussionsHere we show that endogenous HER2 interacts with Beclin 1 in multiple HER2 +breast cancer cells and inhibits autophagy. Mice with a knock-in mutation in Becn1 (Becn1F121A) that leads to increased basal autophagy are protected from mammary tumorigenesis when crossed with mammary-specific HER2 transgenic mice, and HER2 fails to inhibit autophagy in primary cells derived from these mice.Moreover, treatment of mice with HER2-positive human breast cancer xenografts with the Tat-Beclin 1 autophagy-inducing peptide inhibits tumour growth as effectively as a clinically used HER2 tyrosine kinase inhibitor (TKI). This inhibition of tumour growth is associated with a robust induction of autophagy, a disruption of HER2/Beclin 1 binding, and a transcriptional signature in the tumours that is distinct from that observed with HER2 TKI treatment.ConclusionThese findings indicate that the HER2-mediated inhibition of Beclin 1 and autophagy likely contributes to HER2-mediated tumorigenesis. They also suggest that strategies to block HER2/Beclin 1 binding and/or increase autophagy may represent a new therapeutic approach for HER2-positive breast cancers.

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