Regulation of breast cancer biomarkers by intrinsic and extrinsic factors

Pallegar, Nikitha K. (2018) Regulation of breast cancer biomarkers by intrinsic and extrinsic factors. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

Cancer metastases are accountable for almost 90% of all human cancer-related deaths including breast cancer (BC). BC is the most common cancer among Canadian women, with one in four women diagnosed per year. BC is a heterogenous disease and is broadly classified into Luminal A (estrogen/progesterone receptor (ER/PR)⁺), Luminal B (ER/PR⁺ and human epidermal growth receptor 2⁺ (HER2⁺)), HER2⁺, and triple negative breast cancer (TNBC, ER-/PR-/HER2⁻). BC heterogeneity and progression are primarily dependent on intrinsic factors such as genetic or epigenetic changes to genes that regulate cell growth and proliferation. In addition, extrinsic factors such as, the extracellular matrix and adipocytes in the surrounding microenvironment contribute to cancer progression and initiation of metastasis. Therefore, the main aim of this thesis was to analyze the contribution of some of the intrinsic and extrinsic factors that regulate BC progression. One known intrinsic factor is CD24; a glycosylphosphatidylinositol-anchored surface glycoprotein that can regulate proliferation and apoptosis of various cell types. Breast cancer stem cells (BCSCs), which can initiate tumor formation, maintain tumor heterogeneity, have high invasive properties, and favor metastasis, have low CD24 expression. Moreover, drug treatment of TNBC tumors can cause a switch from CD24⁺ to CD24⁻ and vice versa exhibiting differential drug resistance in these patients. In order to better understand the role of CD24, I first analyzed the CD24 gene, and found that the sequence of the mature peptide, but not the genomic structure is conserved over 200 million years. Next, I studied the regulation of CD24 expression by the oncogenic Ras pathway and found that Ras is essential for suppression of CD24 surface expression. Extrinsic factors, such as adipocytes, can also contribute to BC progression and metastasis. To study this, I developed a 3-dimensional co-culture system to mimic the in vivo interactions between BC cells and adipocytes. I found that adipocytes promote a mesenchymal-to-epithelial-like transition in BC cells suggesting that secondary tumour formation might be promoted by adipocytes. Overall, these data will aid in understanding the intrinsic and extrinsic factors that should be considered in the future development of combination drug treatments to successfully cure BC.

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