Date of Graduation

8-2014

Document Type

Thesis (MS)

Program Affiliation

Biomedical Sciences

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Karen Lu, MD

Committee Member

Rosemarie Schmandt, PhD

Committee Member

Russell Broaddus, MD, PhD

Committee Member

Samuel Mok, PhD

Committee Member

Kwong K. Wong, PhD

Abstract

Hormonal therapy remains a first line option for the treatment of recurrent endometrial cancer (EC), however, many tumors demonstrate de novo or acquired resistance. Member kinases of the PI3K/AKT and Ras/MAPK pathways activate estrogen receptor α (ERα) independent of estrogen, however, few studies have evaluated the role of the Ras/MAPK pathway in predicting response to hormonal therapy in EC. The aims of this project were to evaluate the role of ligand independent activation of ERα in EC and to explore therapeutic implications for the treatment of recurrent EC.

A xenograft model for recurrent EC was used to evaluate the effect of treatment with letrozole, everolimus, and metformin in vivo. These studies demonstrated that tumors with an activating KRas mutation are resistant to treatment with letrozole even in combination with everolimus. Tumor growth and cellular proliferation were reduced only after the addition of metformin.

To assess signaling through ERα, cells with and without an activating KRas mutation were stimulated with estradiol and phosphorylation at serine 167 (ser167) and serine 118 (ser118) evaluated. KRas mutant cells had decreased expression of ERα and this decrease in expression was mirrored in functional proteomic analysis. KRas mutant cells had no detectable phosphorylation at ser167 and decreased phosphorylation at ser118 in response to estradiol stimulation, which was restored following treatment with a MEK inhibitor.

To address the functional consequence of differential estrogen signaling expression of estrogen induced genes and cell viability assays were evaluated. Following treatment with a MEK inhibitor, mutant KRas cells had increased expression of estrogen-induced genes compared to cells with wild type KRas, mirroring the increase in phosphorylation at ser167 and ser118. Treatment of mutant KRas cells with a MEK inhibitor in the presence of estradiol had no effect, while treatment with a MEK inhibitor in the absence of estradiol resulted in decreased cell viability.

Endometrial cancer cells harboring KRas mutations are functionally ER negative and are resistant to treatment with hormonal therapy. The addition of hormonal therapy to MEK inhibition may provide added benefit for patients with recurrent endometrial cancer compared to either therapy alone, with an improved side effect profile.

Keywords

Endometrial cancer, PTEN, KRas, estrogen receptor, crosstalk

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