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Publication Date

2014-04-23

Availability

UM campus only

Embargo Period

2014-04-23

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Cancer Biology (Medicine)

Date of Defense

2014-01-08

First Committee Member

Dorraya El-Ashry

Second Committee Member

Marc E. Lippman

Third Committee Member

Ralf Landgraff

Fourth Committee Member

Jennifer Clarke

Fifth Committee Member

Amjad Farooq

Abstract

ER-positive primary breast cancers can often be successfully treated with surgery followed by adjuvant anti-estrogen therapies. ER-negative breast cancers do not depend on estrogen signaling for their growth, proliferation, and survival, and are insensitive to anti-estrogen therapies. ER-negativity is associated with earlier disease mortality and overall poorer clinical outcomes. It is imperative to understand what drives the ER-negative phenotype in breast cancer, and elucidation of mechanisms leading to loss of ER or estrogen independence may identify novel avenues of therapeutic intervention for patients with breast cancer. Hyperactivation of ERK1/2 MAPK signaling has been identified as one pathway leading to loss of estrogen receptor, and contributes to progression from an ER-positive, estrogen dependent disease to an ER-negative, estrogen independent breast cancer. MicroRNAs are known to play important roles in the biology of normal cells and tissues, and are also known to facilitate pathological processes. Here we describe the identification of a microRNA signature associated with hyperactive MAPK signaling in breast cancer (hMAPK-microRNA signature), and we present statistical and molecular analysis of this signature regarding behavior and outcome in breast cancer. The data presented here suggest that microRNAs contribute to the establishment of ER-negativity and to aggressive characteristics of breast cancer. The sub-signature of hMAPK-microRNAs which significantly associates with poor clinical outcome suggests that stratification of breast cancer patients based on expression of these hMAPK-microRNAs may provide important prognostic information and may be indicative of response to ER-targeted therapy in patients with ER-positive breast cancer.

Keywords

Breast Cancer; MicroRNA; estrogen receptor; MAPK; growth factors

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