Abstract

The autocrine-paracrine effects of IGF2 are important in the growth and differentiation of normal breast. In breast cancer (BC), IGF2 is initially stimulated by estrogen, progesterone and prolactin to regulate proliferation and cancer progression. These actions are mediated by the IGF-1R and insulin receptor A (IR-A) both members of the tyrosine- kinase receptors family. The activation of Estrogen Receptor (ER) is also very important in BC growth and progression. As BC progresses to estrogen-independent growth, the IGF-1R and the estrogen receptor (ER) interact in crosstalk mechanisms that are synergistic and results in enhanced activation of both receptors signaling cascades. This mechanism plays a central role in the transition of estrogen-dependent to estrogen-independent breast cancer (BC) progression. Basal-like BC (BLBC) is a sub-group of estrogen-independent tumors that have a very aggressive clinical behavior and are resistant to hormone-based therapy resulting in reduced disease-free survival period and increasing the mortality of breast cancer (BC) patients. Our BC research team has elucidated how IGF2 crosstalk signaling results in the activation of ER pathways independent of estrogen. Central to our investigation is how this mechanism is associated to the survival disparity observed among African American (AA) BC patients. BLBC accounts for nearly 15-20% of all breast cancers, however it represents 45% of all BC observed in AA patients. Analyses of subcellular compartments, Western-Blot and siRNA demonstrated that IGF2 activates ER-α and ER-β in ER negative BLBC cells Hs578t and CRL-2335. Our studies show that both IGF-1R and IR crosstalk with ER-α and ER-β promoting BLBC progression. This novel mechanism offers new therapeutic targets that will significantly impact treatment and diagnosis of BLBC patients.

LLU Discipline

Microbiology and Molecular Genetics

Department

Basic Sciences

School

School of Medicine

First Advisor

De Leon, Daisy D.

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

January 2011

Date (Title Page)

3-1-2011

Language

English

Library of Congress/MESH Subject Headings

Estrogen; Breast Cancer;

Subject - Local

Estrogen receptors; Breast cancer cells

Type

Dissertation

Page Count

97 p.

Digital Format

Application/PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses & Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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