File(s) under embargo

1

year(s)

5

month(s)

11

day(s)

until file(s) become available

Examining the Role of Cholesterol in Src Activation and Effect on Downstream Signaling Using Biosensors

thesis
posted on 01.12.2021, 00:00 by Arthur A Ralko
Breast cancer is one of the most common cancers among women. While advances have been made in breast cancer treatments, intrinsic heterogeneity and complexity of the disease leave some patients with limited treatment options. One subclass, triple-negative breast cancer (TNBC), which constitutes about 15% of total breast cancer cases, lacks the three common treatment targets – estrogen, progesterone, and Her2 receptors. Overall, TNBC is more aggressive and has a higher relapse rate and a worse prognosis than other types of breast cancer. Further complicating the treatment of TNBC is the degree of genetic heterogeneity among TNBC cells, which necessitates the identification of new molecular targets for a tailored, cell type-specific therapy for TNBC. Accumulating evidence has linked cholesterol to the progression of breast cancer but epidemiological and clinical studies have produced conflicting data, underscoring the need to elucidate cellular signaling pathways and molecular mechanisms directly linking cholesterol to breast cancer cell progression. Based on our recent work showing that the cholesterol level at the inner plasma membrane (IPM) controls the proliferative signaling activity of cells, we investigated the link between IPM cholesterol levels of TNBC cells and their oncogenic signaling activity. By means of our ratiometric fluorescence sensor-based quantitative cholesterol imaging technology, we determined the IPM cholesterol levels of several TNBC cells and found that they consistently higher IPM cholesterol levels than other breast cancer cells and primary breast cells, leading to constitutive activation of Src kinase. Our biophysical studies showed that Src can directly interact with cholesterol via its Src-homology 2 (SH2) domain. Further mechanistic investigation revealed that IPM cholesterol-mediated activation of Src led to activation of Ras-mitogen activated protein kinase (MAPK) signaling axis, which is responsible for aggressive phenotypes of TNBC cells, including cell migration and proliferation. We also developed small molecule inhibitors for Src-cholesterol binding that can potentially serve as a drug candidate for TNBC. Collectively, our study demonstrates a new mechanistic link between cholesterol and TNBC progression and offers a novel and exciting possibility to expand treatment options for this aggressive form of breast cancer.

History

Advisor

Cho, Wonhwa

Chair

Cho, Wonhwa

Department

Chemistry

Degree Grantor

University of Illinois at Chicago

Degree Level

Doctoral

Degree name

PhD, Doctor of Philosophy

Committee Member

Karginov, Andrei Yang, Xiaojing Hu, Ying Miller, Lawrence

Submitted date

December 2021

Thesis type

application/pdf

Language

en

Usage metrics

Categories

Exports