Abstract

Approximately 40% of estrogen receptor positive breast cancer (BC) patients develop resistance to endocrine therapy (ET) agents like tamoxifen (Tam). Resistance promotes metastasis, recurrence, and death since metastatic BC is often incurable. Breast cancer stem cells (CSCs) greatly contribute to disease progression and drug resistance. We previously showed that aryl hydrocarbon receptor (AhR) agonist aminoflavone (AF) inhibits the expression of CSC biomarker α6-integrin (ITGA6) to disrupt the formation of endocrine-sensitive and -resistant luminal A mammospheres. In this study, we performed miRNAsequencing analysis of luminal A MCF-7 and MCF-7TamR mammospheres before and after AF treatment to further develop the mechanism of AF-mediated antistemness activity. AF significantly upregulated over 70 miRNAs in Tam-sensitive mammospheres, including miR125b-2-3p. In TamR mammospheres, AF significantly upregulated 63 miRNAs including miR135a-5p. Both miRNAs are predicted stemness gene regulators. miR125b-2-3p mimic inhibited the expression of ITGA6 in MCF-7 cells and mammospheres while antagomiR125b-2-3p reversed AF-mediated suppression of ITGA6. Both miRNA mimics regulated stemness properties in endocrine-sensitive and -resistant MCF-7 cells. miR125b- 2-3p mimic decreased proliferation, migration, and mammosphere formation, while the antagomiR125b-2-3p increased proliferation and mammosphere formation in ET-sensitive cells. miR135a-5p mimic reduced proliferation and mammosphere formation in ET-resistant cells while the antagomiR increased these properties in ET-sensitive cells. AF induced AhR- and miR125b2-3pdependent anti-proliferation, anti-migration, and mammosphere disruption in ET-sensitive cells. AF induced miR135a-5p-dependent anti-proliferation, and mammosphere disruption in ET-resistant cells. Our findings suggest both miRNAs are anti-stemness tumor suppressors in ET-sensitive and -resistant MCF-7 cells and that AF upregulates these miRNAs to reduce CSCs via mechanisms that rely at least partially on AhR in luminal A breast cancer cells.

LLU Discipline

Pharmacology

Department

Pharmacology

School

School of Medicine

First Advisor

Juli Unternaehrer

Second Advisor

Eileen Brantley

Third Advisor

Salma Khan

Fourth Advisor

Gayathri Nagaraj

Fifth Advisor

Charles Wang

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2022

Date (Title Page)

5-2022

Language

English

Library of Congress/MESH Subject Headings

Breast Neoplasms; MicroRNAs; aminoflavone; MCF-7 Cells; Biomarkers

Type

Dissertation

Page Count

xx, 268 p.

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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