Abstract

Approximately 40% of estrogen receptor positive (ER+) breast cancer patients develop resistance to standard of care agent tamoxifen, while ER negative (ER-) breast cancer patients are intrinsically resistant to tamoxifen. Resistance often promotes metastasis, recurrence and death. Tumor-initiating cells (TICs) represent key contributors to resistance and adhesion protein α6-integrin is a putative TIC biomarker. Investigational agent Aminoflavone (AF) demonstrates efficacy against breast cancer cells irrespective of ER status. Interestingly, we found tamoxifen resistant (TamR) cells and tumors exhibited elevated α6-integrin expression in comparison to their tamoxifen sensitive counterparts. AF effectively disrupted mammospheres enriched for TICs and reduced α6-integrin levels in tamoxifen sensitive and TamR cells. AF further inhibited α6-integrin’s pro-cancer signaling in TamR cells. Additionally, AF altered the miRNA expression profile of tamoxifen sensitive and TamR mammosphere-derived cells. Our data suggest that AF inhibits α6-integrin signaling and alters the expression of specific miRNAs to reduce TIC capacity and counteract tamoxifen resistance.

LLU Discipline

Pharmacology

Department

Basic Sciences

School

School of Medicine

First Advisor

Brantley, Eileen

Second Advisor

Nagaraj, Gayathri

Third Advisor

Soto, Ubaldo

Fourth Advisor

Wang, Charles

Fifth Advisor

Zhang, Lubo

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2018

Date (Title Page)

8-2018

Language

English

Library of Congress/MESH Subject Headings

flavonoids; Amines; Breast Neoplasms; Breast Cancer

Subject - Local

Tamoxifen Resistant Cells; Estrogen Receptor Positive

Type

Dissertation

Page Count

171

Digital Format

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 and Dissertations

Collection Website

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

Repository

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

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