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Authors: Michaela J. Higgins, Julia A. Beaver, Hong Yuen Wong, John P. Gustin, Josh D. Lauring, Joseph P. Garay, Hiroyuki Konishi, Morassa Mohseni, Grace M. Wang, Justin Cidado, Danijela Jelovac, David P. Cosgrove, Akina Tamaki, Abde M. Abukhdeir and Ben Ho Park

Michaela J. Higgins

The Johns Hopkins University School of Medicine, Baltimore, MD

Julia A. Beaver

The Johns Hopkins University School of Medicine, Baltimore, MD

Hong Yuen Wong

The Johns Hopkins University School of Medicine, Baltimore, MD

John P. Gustin

The Johns Hopkins University School of Medicine, Baltimore, MD

Josh D. Lauring

The Johns Hopkins University School of Medicine, Baltimore, MD

Joseph P. Garay

The Johns Hopkins University School of Medicine, Baltimore, MD

Hiroyuki Konishi

The Johns Hopkins University School of Medicine, Baltimore, MD

Morassa Mohseni

The Johns Hopkins University School of Medicine, Baltimore, MD

Grace M. Wang

The Johns Hopkins University School of Medicine, Baltimore, MD

Justin Cidado

The Johns Hopkins University School of Medicine, Baltimore, MD

Danijela Jelovac

The Johns Hopkins University School of Medicine, Baltimore, MD

David P. Cosgrove

The Johns Hopkins University School of Medicine, Baltimore, MD

Akina Tamaki

The Johns Hopkins University School of Medicine, Baltimore, MD

Abde M. Abukhdeir

Corresponding author: aabukhd@hotmail.com
The Johns Hopkins University School of Medicine, Baltimore, MD

Ben Ho Park

Corresponding author: bpark2@jhmi.edu
The Johns Hopkins University School of Medicine, Baltimore, MD

Abstract:
A high frequency of somatic mutations has been found in breast cancers within the gene encoding the catalytic p110α subunit of PI3K, PIK3CA. Using isogenic human breast epithelial cells, we have previously demonstrated that oncogenic PIK3CA "hotspot" mutations predict for response to the toxic effects of lithium. However, other somatic genetic alterations occur within this pathway in breast cancers, and it is possible that these changes may also predict for lithium sensitivity. We overexpressed the epidermal growth factor receptor (EGFR) into the non-tumorigenic human breast epithelial cell line MCF-10A, and compared these cells to isogenic cell lines previously created via somatic cell gene targeting to model Pten loss, PIK3CA mutations, and the invariant AKT1 mutation, E17K. EGFR overexpressing clones were capable of cellular proliferation in the absence of EGF and were sensitive to lithium similar to the results previously seen with cells harboring PIK3CA mutations. In contrast, AKT1 E17K cells and PTEN -/- cells displayed resistance or partial sensitivity to lithium, respectively. Western blot analysis demonstrated that lithium sensitivity correlated with significant decreases in both PI3K and MAPK signaling that were observed only in EGFR overexpressing and mutant PIK3CA cell lines. These studies demonstrate that EGFR overexpression and PIK3CA mutations are predictors of response to lithium, whereas Pten loss and AKT1 E17K mutations do not predict for lithium sensitivity. Our findings may have important implications for the use of these genetic lesions in breast cancer patients as predictive markers of response to emerging PI3K pathway inhibitors.

See commentary: Treating PIK3CA and EGFR overexpressing breast cancers with lithium citrate

Received: November 5, 2010; Accepted: November 18, 2010

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