Biomedical Sciences ETDs

Author

Erin Zekas

Publication Date

7-1-2014

Abstract

17β-estradiol (estrogen) has been demonstrated to regulate survival in breast cancer cells, which is partially mediated by its nuclear receptors ERα and ERβ and the G protein-coupled estrogen receptor (GPER). We previously established that estrogen can activate the phosphoinositide 3-kinase (PI3Kinase) prosurvival pathway via GPER stimulation resulting in PIP3 generation within the nucleus of breast cancer cells; the mechanism for this is still unclear. PIP3 generation results in Akt activation, which is known to inactivate FOXO3a, a proapoptotic transcription factor that translocates from the nucleus to the cytoplasm upon inactivation resulting in a decrease in proapoptotic gene expression and consequently an increase in cell survival. Here, utilizing a FoxO3-GFP construct, we report FOXO3a inactivation as a result of GPER stimulation by E2 and the GPER-selective agonist G-1 in the estrogen-responsive breast cancer cell line MCF7 and that ERα is not required. The p110α catalytic subunit of PI3Kinase, and the transactivation of the EGFR constitute the mechanism by which GPER inactivation of FOXO3a occurs. Additionally, E2 and G-1 stimulation of MCF7 cells results in a decrease in caspase activation compared to negative control. This suggests, in part, that GPER stimulation is required for survival of breast cancer cells and that GPER expression and FOXO3a localization should be utilized as prognostic markers in breast cancer treatments. Furthermore, our results indicate a need for GPER antagonists in GPER positive breast cancers in order to counteract GPER related prosurvival effects in combination with chemotherapeutic drug treatments.

Keywords

Breast Cancer Cell Signaling

Sponsors

Spatial Temporal Modeling Center at the University of New Mexico, National Institutes of Health

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Advisor

Prossnitz, Eric

First Committee Member (Chair)

Wandinger-Ness, Angela

Second Committee Member

Hathaway, Helen

Third Committee Member

Lidke, Diane

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