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Breast Cancer Research and Treatment

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01-12-2016 | Preclinical study

Transcriptome- and proteome-oriented identification of dysregulated eIF4G, STAT3, and Hippo pathways altered by PIK3CA ^H1047R in HER2/ER-positive breast cancer

Authors: Feixiong Cheng, Junfei Zhao, Ariella B. Hanker, Monica Red Brewer, Carlos L. Arteaga, Zhongming Zhao

Published in: Breast Cancer Research and Treatment | Issue 3/2016

Abstract

Purpose

Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in human breast cancer. Furthermore, PIK3CA mutations are commonly associated with resistance to anti-epidermal growth factor receptor 2 (HER2) or anti-estrogen receptor (ER) agents in HER2 or ER positive (HER2⁺/ER⁺) breast cancer. Hence, deciphering the underlying mechanisms of PIK3CA mutations in HER2⁺/ER⁺ breast cancer would provide novel insights into elucidating resistance to anti-HER2/ER therapies.

Methods

In this study, we systematically investigated the biological consequences of PIK3CA ^H1047R in HER2⁺/ER⁺ breast cancer by uniquely incorporating mRNA transcriptomic data from The Cancer Genome Atlas and proteomic data from reverse-phase protein arrays.

Results

Our integrative bioinformatics analyses revealed that several important pathways such as STAT3 and VEGF/hypoxia were selectively altered by PIK3CA ^H1047R in HER2⁺/ER⁺ breast cancer. Protein differential expression analysis indicated that an elevated eIF4G might promote tumor angiogenesis and growth via regulation of the hypoxia-activated switch in HER2⁺ PIK3CA ^H1047R breast cancer. We observed hypo-phosphorylation of EGFR in HER2⁺ PIK3CA ^H1047R breast cancer versus HER2⁺PIK3CA^wild-type (PIK3CA ^WT). In addition, ER and PIK3CA ^H1047R might cooperate to activate STAT3, MAPK, AKT, and Hippo pathways in ER⁺ PIK3CA ^H1047R breast cancer. A higher YAP_pS127 level was observed in ER⁺ PIK3CA ^H1047R patients than that in an ER⁺ PIK3CA ^WT subgroup. By examining breast cancer cell lines having both microarray gene expression and drug treatment data from the Genomics of Drug Sensitivity in Cancer and the Stand Up to Cancer datasets, we found that the elevated YAP1 mRNA expression was associated with the resistance of BCL-2 family inhibitors, but with the sensitivity to MEK/MAPK inhibitors in breast cancer cells.

Conclusions

In summary, these findings shed light on the functional consequences of PIK3CA ^H1047R-driven breast tumorigenesis and resistance to the existing therapeutic agents in HER2⁺/ER⁺ breast cancer.

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Title: Transcriptome- and proteome-oriented identification of dysregulated eIF4G, STAT3, and Hippo pathways altered by PIK3CA H1047R in HER2/ER-positive breast cancer
Authors: Feixiong Cheng
Junfei Zhao
Ariella B. Hanker
Monica Red Brewer
Carlos L. Arteaga
Zhongming Zhao
Publication date: 01-12-2016
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 3/2016
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-016-4011-9

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