Digital Commons Network^™

The Role Of Notch-1-Mediated Repression Of Pten On Growth And Cancer Stem Cell Survival In Trastuzumab Resistant, Her2+ Breast Cancer, Andrew Thomas Baker

Dissertations

Trastuzumab targets the ErbB2 (HER2) receptor on breast cancer cells to attenuate HER2 driven tumor formation. Trastuzumab reduces both downstream PI3K/Akt and MAPK pathway signaling as well as the breast cancer stem cell (BCSC) population. BCSCs are hypothesized to be responsible for tumor recurrence, metastasis, as well as drug resistance. Today, resistance to trastuzumab remains a major clinical problem for women diagnosed with HER2+ breast cancer. Attenuation of PI3K/Akt and MAPK pathways may occur through the tumor suppressor, PTEN. Women with HER2+ breast tumors expressing less PTEN and increased PI3K/Akt or MAPK activity have worse overall outcome. Previously we have …

Novel Role Of Erbb-2 In Inhibition Of Jagged-1-Mediated Trans-Activation Of Notch In Breast Cancer, Kinnari Pandya

Dissertations

The ErbB-2 gene is amplified and the resulting protein product overexpressed in 15-30% of breast tumors, and associated with aggressive behavior and poor overall survival. Currently, there are two FDA approved therapies targeting ErbB-2 for the treatment of ErbB-2 positive breast cancer: trastuzumab, a humanized monoclonal antibody is directed against the extracellular domain of ErbB-2 and lapatinib, a dual EGFR/ErbB-2 tyrosine kinase inhibitor. Unfortunately, anti-ErbB-2 therapy resistance remains a major problem in metastatic breast cancer. Our data suggested that gene amplification or overexpression of ErbB-2 inhibits Notch-1 transcriptional activity and trastuzumab or lapatinib increased

Notch-1 transcriptional activity. Furthermore, Notch-1 is …

Role Of Notch Signaling In T Cell Polarization, Shilpa Keerthivasan

Dissertations

The differentiation of CD4+ T cells to different effector lineages in response to pathogenic stimuli is the core of the adaptive immune system. One of the effector subsets recently discovered is Thelper 17 (Th17) and it plays a predominant role in autoimmune diseases and inflammatory disorders.

In my thesis, I aimed to study the role of Notch cell surface receptors in Th17 differentiation. Using in vitro Th17 differentiation assays of human naïve CD4+ T cells, I have shown that Notch signaling, particularly Notch1, plays a crucial role in Th17 polarization. By using pharmacological inhibitors and specific knockdown of Notch1, I …

Notch-1 Specifically Activates Erk1/2 In Multiple Breast Cancer Subtypes, Allison Schuyler Rogowski

Master's Theses

Notch-1 is a cell fate regulatory protein and a potent breast oncogene. Notch-1 and its ligand Jagged-1 are over-expressed in human breast cancers that are associated with poor overall survival (Reedijk, Odorcic et al. 2005). Deregulated Notch signaling may contribute to tumorigenesis by increasing proliferation, inhibiting differentiation, and preventing apoptosis (Miele, Golde et al. 2006). The mitogen-activated protein kinase (MAPK) pathway is a critical cell signaling pathway that has been implicated in the development and progression of cancer (Hanahan and Weinberg 2000). Four major MAPK pathways are involved in both cell growth and apoptosis. The regulation of these pathways is …

Notch Signaling Is Important In The Survival, Proliferation, And Self-Renewal Of The Putative Breast Cancer Stem Cell Population, Peter Grudzien

Dissertations

Numerous studies have identified stem-like cells, termed cancer stem cells (CSCs), in breast tumors and established cell lines. It has been hypothesized that CSCs are responsible for breast cancer formation, progression and recurrence; therefore, a deeper understanding of the signaling pathways regulating CSC survival will benefit development of novel therapeutic strategies. Notch signaling, which is dysregulated in breast cancer and has been implicated in mammary stem cell self-renewal, and can be effectively blocked by gamma-secretase inhibitors (GSIs). While GSIs are currently in clinical trials for breast cancer, it is not fully understood how these compounds will affect CSCs or if …