Oncotarget

Research Papers:

Differential gene expression and AKT targeting in triple negative breast cancer

Feng-Mao Lin, Susan E. Yost, Wei Wen, Paul H. Frankel, Daniel Schmolze, Pei-Guo Chu, Yate-Ching Yuan, Zheng Liu, John Yim, Zhen Chen _ and Yuan Yuan _

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Oncotarget. 2019; 10:4356-4368. https://doi.org/10.18632/oncotarget.27026

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Abstract

Feng-Mao Lin1, Susan E. Yost2, Wei Wen3, Paul H. Frankel4, Daniel Schmolze5, Pei-Guo Chu5, Yate-Ching Yuan6, Zheng Liu6, John Yim3, Zhen Chen1 and Yuan Yuan2

1 Department of Diabetes Complications and Metabolism, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA

2 Department of Medical Oncology and Therapeutic Research, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA

3 Department of Surgery, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA

4 Department of Biostatistics, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA

5 Department of Pathology, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA

6 Bioinformatics Core Facility, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA

Correspondence to:

Yuan Yuan,email: yuyuan@coh.org
Zhen Chen,email: zhenchen@coh.org

Keywords: AKT; differential expression; AKT targeting; TNBC

Received: April 10, 2019     Accepted: May 30, 2019     Published: July 09, 2019

ABSTRACT

Background: Metastatic triple negative breast cancer (mTNBC) is a heterogeneous disease with poor prognosis. Molecular evolution of TNBC through chemotherapy selection pressure is well recognized but poorly understood. PI3K/AKT/mTOR is one of the most commonly identified oncogenic-driver pathways in breast cancer. The current study is designed to understand the genomic and transcriptomic changes, focusing on the PI3K/AKT/mTOR pathway alterations in paired primary and metastatic TNBCs.

Results: Genomic analysis of 7 paired specimens identified 67 known mutations including those from the following signaling pathways: cell cycle, p53, PI3K/AKT/mTOR, RAS/MAPK, and RTK/GF. Principle coordinate analysis (PCoA) identified 4 distinctive molecular groups based on the gene expression patterns of PI3K/AKT/mTOR pathway. Key differentially-expressed genes included AKT3, GSK3B, GNA11, PI3KR1, and GNAQ. Importantly, AKT-targeted therapy showed efficacy in a patient-derived xenograft (PDX) model of TNBC in vivo.

Conclusion: Genomic discordance of paired primary and metastatic TNBCs was identified, with significant increase in tumor proliferation pathways seen in metastases. Among the differentially expressed genes, AKT3 can potentially serve as a target for novel combination therapy for treatment of metastatic TNBC.

Methods: Paired specimens from 10 patients with TNBCs were identified through an IRB-approved protocol (2002–2015). FoundationOneTM sequencing was performed for genomic profiling, and Affymetrix Human Genechip 2.0st was used for mRNA expression profiling. The similarity among samples was calculated based on Pearson correlation coefficients, which were used to construct hierarchical clustering and heat maps.


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