ErbB2 inhibition by lapatinib promotes degradation of mutant p53 protein in cancer cells.

Dun Li,Natalia D Marchenko

doi:10.18632/oncotarget.12878

Abstract

Mutations in the p53 tumor suppressor gene are the most prevalent genetic events in human Her2-positive breast cancer and are associated with poor prognosis and survival. Human clinical data and our in vitro and in vivo studies strongly suggest potent oncogenic cooperation between mutant p53 and Her2 (ErbB2). Yet, the translational significance of mutant p53 in Her2 positive breast cancer, especially with respect to Her2-targeted therapies, has not been evaluated. Our previous work identified novel oncogenic activity of mutant p53 whereby mutp53 amplifies ErbB2 signaling via the mutp53-HSF1-ErbB2 feed-forward loop. Here we report that pharmacological interception of this circuit by ErbB2 inhibitor lapatinib downregulates mutant p53 in vitro and in vivo. We found that ErbB2 inhibition by lapatinib inhibits transcription factor HSF1, and its target Hsp90, followed by mutant p53 degradation in MDM2 dependent manner. Thus, our data suggest that mutant p53 sensitizes cancer cells to lapatinib via two complementary mechanisms: mutant p53 mediated amplification of ErbB2 signaling, and simultaneous annihilation of both potent oncogenic drivers, ErbB2 and mutant p53. Hence, our study could provide valuable information for the optimization of therapeutic protocols to achieve superior clinical effects in the treatment of Her2 positive breast cancer.

Highlights

Recent evidence suggests that mutations in the p53 tumor suppressor gene are recognized as “driver” mutations in cancer [1], additional tumor-promoting events, such as cooperation with other oncogenic pathways, are emerging as essential mechanisms of cancer progression [2].The human epidermal growth factor receptor-2 (Her2, ErbB2) is frequently overexpressed in human breast cancer, which is associated with poor survival [3]
We found that mutp53 physically interacts with and enhances the transcriptional activity of HSF1 (Heat Shock Transcription Factor 1), the master transcriptional regulator of heat shock proteins (HSP) including Hsp90
To determine whether the observed effects are dependent on the type of p53 mutation, we established mammary epithelial cells (MECs) from mutp53 R248Q/-;ErbB2 mice

Summary

Introduction

Recent evidence suggests that mutations in the p53 tumor suppressor gene are recognized as “driver” mutations in cancer [1], additional tumor-promoting events, such as cooperation with other oncogenic pathways, are emerging as essential mechanisms of cancer progression [2].The human epidermal growth factor receptor-2 (Her, ErbB2) is frequently overexpressed in human breast cancer, which is associated with poor survival [3]. Female patients with germline p53 mutations (Li-Fraumeni syndrome [LFS]) are especially prone to the Her subtype of breast cancer (up to 83% of all breast cancer in LFS women [5, 6] compared to 20% in sporadic breast cancer [1]), suggesting cooperative co-selection of these potent oncogenes during Her breast cancer progression. This strongly suggests a causative connection between p53 mutations and Her breast cancer development. No systematic studies have been done to assess mutant p53 (mutp53)’s significance in Her breast cancer development and therapy

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Results

Conclusion