NYMC Student Theses and Dissertations

Date of Award

12-31-2025

Document Type

Doctoral Dissertation - Open Access

Degree Name

Doctor of Philosophy

Department

Biochemistry and Molecular Biology

First Advisor

Ken Lerea Ph.D

Second Advisor

Shuai Gao Ph.D

Third Advisor

Jian Li Ph.D

Abstract

Global changes in gene expression are orchestrated by an array of transcription factors regulated by both extracellular and intracellular signals. The mechanistic target of rapamycin (mTOR) is a protein kinase that ubiquitously mediates signaling networks across every cell type, in two active complexes, mTORC1 and mTORC2. By phosphorylating its downstream targets, these classically cytosolic complexes regulate protein homeostasis, metabolism, cell growth, proliferation and survival. However, evidence from prostate cancer studies reveals mTOR and its partners can occupy the nucleus, where its interaction with chromatin (in complex with transcription factors) has been shown to regulate gene expression at the level of transcription. A knowledge gap remains regarding the role of mTOR as a transcriptional regulator within the nucleus, particularly in the context of breast cancer. Our lab has previously shown evidence of a direct interaction between mTORC1 and estrogen receptor-α (ERα), demonstrating both direct phosphorylation and activation of ERα by mTORC1 and its effector kinase S6K1 (Ribosomal protein S6 kinase beta-1). We have also reported estrogen-driven colocalization of mTORC1 and ERα within the nucleus in ER+ breast cancer cell lines. Following its nuclear fate in response to estrogen, this study aims to shed further light on the role of mTOR activity in estrogen-mediated gene control. Using the estrogen receptor positive (ER+) MCF7 cancer model and mTOR complex inhibitors, we dissect mTOR’s activity with respect to nuclear localization, chromatin interaction, and gene expression, in response to estrogen- this along with in-depth, meta-bioinformatic analyses of relevant protein-DNA interactions. Our long-term goal is to understand the transcriptional role of the mTOR-ERα axis and how it has been contributing to the progression of ER+ breast cancer all along.

Disciplines

Medicine and Health Sciences

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