Dissertation/Thesis Abstract

Translational Reprogramming by eIF4E in Tamoxifen-Resistant ER+ Breast Cancer
by Geter, Phillip A., Ph.D., New York University, 2018, 221; 10604789
Abstract (Summary)

The majority of breast cancers express the estrogen receptor (ER+) and are treated with anti-estrogen therapies, particularly the inhibitor tamoxifen. However, many women treated with tamoxifen develop resistance, leading to metastatic disease, which is responsible for the majority of breast cancer deaths. Using small molecule inhibitors, phospho-mimetic proteins, tamoxifen sensitive and resistant breast cancer cells, a patient derived tamoxifen-resistant xenograft model, and genome-wide transcription and translation studies, we show that tamoxifen resistance is mediated by selective mRNA translational reprogramming. Tamoxifen resistant translation is mediated by increased expression of translation factor eIF4E, increased mTOR activity to promote eIF4E availability, and increased MNK activity to promote eIF4E Ser209 phosphorylation. Tamoxifen re-sensitization is restored only by reducing eIF4E expression or mTOR activity and blocking MNK1-directed eIF4E phosphorylation. Of the translationally upregulated mRNAs specific to tamoxifen resistant cells, we show that Runx2, which encodes a regulator of ER signaling that antagonizes estrogen responses and promotes breast cancer metastasis, significantly increases tamoxifen resistance and restores sensitivity when silenced. Moreover, tamoxifen resistant but not sensitive patient ER+ breast cancer specimens demonstrate strongly increased levels of mTOR and MNK activity and eIF4E protein. eIF4E levels, availability and phosphorylation therefore promote tamoxifen resistance in ER+ breast cancer through translatome reprogramming.

Indexing (document details)
Advisor: Schneider, Robert J.
Commitee: Bromberg, Jacqueline, Garabedian, Michael, Mohr, Ian, Possemato, Richard
School: New York University
Department: Basic Medical Science
School Location: United States -- New York
Source: DAI-B 79/08(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Molecular biology, Cellular biology, Oncology
Keywords: Breast cancer, Cap-dependent translation, Translation initiation, Translational control, eIF4E
Publication Number: 10604789
ISBN: 978-0-355-77334-7
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