Graduation Date

Spring 5-7-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Genetics, Cell Biology & Anatomy

First Advisor

Vimla Band, Ph.D.

Abstract

Breast cancer is the second most leading cause of death among women in the United States. Several environmental and genetic factors contribute to the pathogenesis of the disease. It is classified into different subtypes based on expression of certain markers as well as that of set of genes that define the disease progression and associated mortality. Identification of various subtypes namely: Luminal-like (Luminal-A, Luminal-B), ErbB2 over-expressing, Basal-like and Claudin low types, showed an association of survival outcomes with that of the corresponding gene expression signatures, thus paving a way for therapeutic intervention. It further emphasizes the importance of nature of gene expression changes characteristic of each subtype in regulating the disease outcome. Another important factor that determines disease phenotype is the nature of cell of origin. As part of my thesis research, I investigated the role of different combination of oncogenes/tumor–suppressor and the nature of cell type in contributing towards phenotypic and pathological differences in development of breast cancer. hTERT immortalized stem/progenitor cell lines K5+/K19- and K5+/K19+ when transformed by combination of triple oncogene/tumor-suppressor -mRas/mp53/wtErbB2 or mRas/mp53/wtEGFR gave rise to heterogeneous primary tumors as well as spontaneous lung metastasis in-vivo upon orthotopic transplantation in mammary glands of immunocompromised NSG mice. Important tumor characteristics such as latency and incidence of primary and metastatic tumors depend on both the nature of cell type and oncogene combination. K5+/K19- over-expressing mRas/mp53/wtEGFR had a significantly late tumor onset than all other tested cell lines. Transformed K5+/K19+ cells overall possess higher anchorage independent growth and metastasis forming ability than K5+/K19- cells. From microarray analysis, we observed that tumors from transformed K5+/K19- cells have a higher EMT gene signature, more so for K5+/K19- over-expressing mRas/mp53/wtErbB2. Tumors from K5+/K19+ cells over-expressing mRas/mp53/wtEGFR express known markers for metastasis in BC, accounting for higher metastasis ability from these tumors. We also observed complete in-vitro transformation and tumor formation from either cell lines following over-expression of mRas/mp53/mPI3K oncogene combination. K5+/K19- or K5+/K19+ cells show distinct EMT upon over-expression of mRas/mp53/mPI3K combination and overall K5+/K19- cells have a higher susceptibility to undergo EMT upon transformation as compared to K5+/K19+ cells.

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