Regulation of estrogen receptor-alpha mediated gene expression and endocrine resistance through estrogen receptor-alpha phosphorylation and micro-RNA in breast cancer

Kim, Kyuri

Permalink

https://hdl.handle.net/2142/24407 Copy

Description

Title

Regulation of estrogen receptor-alpha mediated gene expression and endocrine resistance through estrogen receptor-alpha phosphorylation and micro-RNA in breast cancer

Author(s)

Kim, Kyuri

Issue Date

2011-05-25T14:38:22Z

Director of Research (if dissertation) or Advisor (if thesis)

Katzenellenbogen, Benita S.

Doctoral Committee Chair(s)

Katzenellenbogen, Benita S.

Committee Member(s)

• Bagchi, Milan K.
• Katzenellenbogen, John A.
• Kemper, Byron W.
• Nardulli, Ann M.

Department of Study

Molecular & Integrative Physl

Discipline

Molecular & Integrative Physi

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• Estrogen Receptor
• Endocrine Resistance
• Breast Cancer
• microRNA
• Phosphorylation

Abstract

Estrogens are associated with the development and progression of breast cancer in addition to their role in normal reproductive physiology, and estrogen receptors (ER) mediate the actions of estrogen in target tissues by regulating the expression of numerous biologically important target genes. The progression of human breast cancer and the development of resistance to endocrine therapies are thought to be associated with ER phosphorylation. We generated multiple combinations of ER phospho-mutants, at residues serine 104, 106, 118, 167, 236, and 305, and examined their impact on receptor half-life, the agonist and antagonist balance of selective estrogen receptor modulators (SERMs) and selective estrogen receptor downregulators (SERDs), the regulation of ER transcriptional activity, and stimulation of cell proliferation in response to estradiol and SERMs/SERD. We showed that changes in ER affecting the phosphorylation status of the receptor greatly impact receptor function and differential SERM and SERD modulated cellular responses that could contribute to resistance to endocrine therapies in breast cancer. We also studied the regulation of microRNAs (miRNAs) by estradiol and growth factors through ER and extracellular signal-regulated kinase 2 (ERK2) in order to understand their physiological impact on breast cancer. We identified nine miRNA- encoding genes harboring overlapping ER and ERK2 binding sites close to their transcription start sites, which require ER and ERK2 for transcriptional induction as well as estradiol- mediated miRNA regulation. We then identified TP63, a target of miR-101, miR-190 and miR- 196a2, and showed that TP63 plays an important role in estradiol- or growth factor-mediated cellular response in breast cancer cells (MCF-7 and MDA-MB-231) by increasing tumor cell growth and in vitro invasion mainly controlled by miR-196a2 action. These results suggest a tumor-suppressive role of miR-196a2 in regulating TP63 expression and the aggressive behavior of breast cancers.

Graduation Semester

2011-05

Permalink

http://hdl.handle.net/2142/24407

Copyright and License Information

Copyright 2011 Kyuri Kim

Owning Collections