Date of Award

2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmacology and Experimental Therapeutics

Abstract

Purpose: Breast cancer is the second leading cause of cancer-related deaths among women worldwide. Human Epidermal Growth Factor Receptor 2 (HER2) positive subtype of breast cancer is driven by a subpopulation of cells possessing stem cell properties of self-renewal and differentiation, known as Cancer Stem Cells (CSCs). CSCs are implicated in tumor growth as well as radiotherapy and chemotherapy associated resistance. Notch receptors promote breast CSCs survival and self-renewal, and overexpression of Notch ligand Jagged1 predicts poor prognosis. We showed previously that Notch could be an important target in trastuzumab/lapatinib resistant HER2+ breast cancer.

Experimental Design: Here, we sought to determine whether anti-HER2 therapy selects for Jagged-1/Notch-dependent CSCs that are responsible for tumor recurrence.

Results: The current study describes a novel role of surface expression of Jagged1 in the enrichment of CSCs. HER2 inhibition selects out a subpopulation of cells that i. express higher Jagged1 on the membrane, ii. interact with Notch-1 and Notch-3 and have higher Notch activation, iii. are enriched for CSCs and iv. predict poor overall cumulative survival in women with HER2+ breast cancer.

Conclusions: The results demonstrate that HER2 blockade in breast cancer cells enriches a Jagged1 high subpopulation that has higher CSC potential and is resistant to HER2 inhibitors. The implications of this work are that dual blockade of Jagged-1 and

HER2 could be more effective than either therapy alone to eliminate both HER2 and Jagged-1 dependent cancer cells.

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