Publication Date

2016-07-26

Availability

Open access

Embargo Period

2016-07-26

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Cancer Biology (Medicine)

Date of Defense

2016-05-26

First Committee Member

Tan A. Ince

Second Committee Member

Dorraya El-Ashry

Third Committee Member

Kerry L. Burnstein

Fourth Committee Member

Joyce Slingerland

Fifth Committee Member

Zafar Nawaz

Abstract

Anti-estrogen and anti-HER2 treatments have been among the first and most successful examples of targeted-therapy for breast cancers. However, around 10-20% of breast cancers lack estrogen receptor (ER) expression and HER2 amplification. Therefore, the treatment of ER-/HER2- Triple Negative Breast Cancer (TNBC) remains a major challenge due to lack of a druggable target. Currently, TNBCs are treated with non-targeted conventional chemotherapy and although they respond initially, less than 30% patients survive beyond 5 years highlighting the need for novel therapeutic strategies for this disease. We previously discovered that approximately two-thirds of TNBCs express Vitamin D Receptor (VDR) and/or Androgen Receptor (AR) and hypothesized that TNBCs that co-express both AR and VDR (HR2-av TNBC) could be treated by targeting both hormone receptors. To evaluate the feasibility of VDR/AR-targeted therapy in TNBC, we characterized 15 different breast cancer cell lines and identified two HR2-av TNBC lines. Surprisingly, we found that AR antagonist inhibited proliferation of most breast cancer cell lines in an AR-independent manner, raising questions regarding their mechanism of action. In contrast, combination treatment of the same cell lines with AR and VDR agonist hormones appeared to inhibit cell proliferation additively in a hormone receptor dependent manner. Moreover, cell viability was further decreased when AR/VDR agonist hormones were combined with chemotherapeutic drugs. The mechanisms of inhibition by AR/VDR agonist hormones included cell cycle arrest and apoptosis in TNBC cell lines. In addition, AR/VDR agonist hormones induced differentiation and inhibited cancer stem cells (CSCs) measured by reduction in tumorsphere formation efficiency, ALDH activity and CSC marker changes. Moreover, alternate AR and VDR ligands are available with enhanced or similar efficacy compared to the traditional agonists but with better side-effect profile. The combination of alternate AR and VDR ligands also showed additive decrease in cell viability in combination with each other as well as with chemotherapeutic agents in vitro. Thus, in summary, AR/VDR targeted agonist hormone therapy can inhibit HR2-av TNBC through multiple mechanisms in a receptor dependent manner and can be combined with chemotherapy.

Keywords

Hormone receptor; triple negative breast cancer; Androgen Receptor; Vitamin D Receptor; Cancer Stem Cells

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