Epigenetic Regulation of Stem Cell Fate Determination in Breast Cancer

Meng-Ju Wu, Purdue University

Abstract

Up to 20% of breast cancers are found to be aggressive, such as triple negative breast cancer, which manifests high tumor grade, rapid metastasis, early recurrence, and high mortality. It is worth noting that aggressive breast tumors are enriched with a high content of cancer stem cells (CSCs), a cell population with acquired perpetuating stemness properties that resemble normal stem cells. Specifically, these CSCs act as the “seed” of the cancer, with the ability to infinitely give rise to the tumor bulk, which accounts for the initiation, progression, metastasis, and recurrence of breast cancer. microRNAs (miRNAs), which are small noncoding RNAs that play pivotal roles in stem cell function during development, provide a new avenue to understanding the regulatory mechanisms in CSCs. The key molecular mechanism governing stem cell fate, which consequently controls the CSC pool, remains elusive. To fill this gap in knowledge, this thesis will focus on elucidating important therapeutic targets that can be used for the eradication of CSCs and develop effective treatment regimens to overcome the therapeutic hurdles of aggressive breast cancer. Here, we show that in response to increased adiposity, elevated leptin activates STAT3-G9a mediated epigenetic reprogramming to promote CSC attributes via the repression of miR-200c expression. Leptin is an adipokine produced by adipocytes, which comprise the most abundant cell type surrounding breast epithelia. Additionally, we also provided the first evidence showing that all-trans retinoic acid (ATRA) induces the interaction and chromatin recruitment of a novel RAR-TET2 complex to epigenetically activate a specific cohort of gene targets, including miR-200c. The miRNA regulator-target gene axis could serve as potential biomarkers for personalized cancer treatment such as to maximize therapeutic efficacy and prevent unnecessary exposure to undesired side effects. Together, these studies provide important therapeutic implications in the attenuation of breast CSCs for the eradication of breast cancer.

Degree

Ph.D.

Advisors

Chang, Purdue University.

Subject Area

Biology|Medicine|Oncology

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