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Breast Cancer Res Treat. 2016 Dec;160(3):457-474. doi: 10.1007/s10549-016-4011-9. Epub 2016 Oct 22.

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

Cheng F1,2,3, Zhao J1,4, Hanker AB5, Brewer MR5, Arteaga CL6,7,8, Zhao Z9,10,11,12.

Author information

1
Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, 37203, USA.
2
Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA.
3
Center for Complex Networks Research, Northeastern University, Boston, MA, 02115, USA.
4
Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
5
Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
6
Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. carlos.arteaga@vanderbilt.edu.
7
Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. carlos.arteaga@vanderbilt.edu.
8
Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. carlos.arteaga@vanderbilt.edu.
9
Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, 37203, USA. zhongming.zhao@uth.tmc.edu.
10
Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA. zhongming.zhao@uth.tmc.edu.
11
Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. zhongming.zhao@uth.tmc.edu.
12
Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. zhongming.zhao@uth.tmc.edu.

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+PIK3CAwild-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 YAPpS127 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.

KEYWORDS:

Bioinformatics; Breast cancer; ER; HER2; PIK3CA; Synergistic interactions

PMID:
27771839
DOI:
10.1007/s10549-016-4011-9
[Indexed for MEDLINE]

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