Breast cancer (BC) is the second most common malignancy in the world and it accounts for 15% of female deaths due to cancer every year. The development of these tumours is regulated by the activities of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Tamoxifen (TAM) is frequently used to treat patients with ER+ BC; however, a recurring problem is the development of resistance and the mechanisms leading up to this event remain unclear. FAM84B is reported to be associated with the development of various cancers such as esophageal squamous cell carcinoma and prostate cancer. The function of the protein is unknown; however, insight towards its mechanism of action has been made through the discovery of its structural similarities with the H-Ras-like suppressor (HRASLS) subfamily of enzymes. We hypothesize that FAM84B upregulation enhances BC tumorigenesis and facilitates the development of TAM resistance in this disease. We observed that both overexpression and knockdown of FAM84B had little effects on cell proliferation; however, the latter reduced the ability of MCF7 cells to form isolated colonies. We performed similar analyses using a FAM84B mutant with deletion of its HRASLS domain and we observed that MCF7 cells expressing this protein showed higher rates of cell proliferation and increased ability to form isolated colonies compared to cells with baseline expression of wild-type FAM84B. These results suggest that FAM84B regulates BC cell proliferation through a complex manner. An analysis of patient-derived BC tissue revealed that FAM84B expression was associated with BC at early stages than later stages, which suggests a possible role of the protein in directing events associated with the early developmental stages of the disease. Additional analyses demonstrated that overexpression and knockdown of FAM84B had little impact on TAM-derived cytotoxicity of MCF7 cells. We observed higher expression of FAM84B in TAM-resistant MCF7 cells in comparison to TAM-sensitive cells, while TAM-resistant and TAM-sensitive xenograft tumours showed similar levels of FAM84B expression. This suggests that the contributions of FAM84B in BC tumorigenesis and resistance to TAM are complex; alternatively, FAM84B may not play a major role in either events. Future studies will be needed to clarify the effects of FAM84B on BC tumorigenesis and progression. / Dissertation / Master of Science (MSc) / Breast cancer (BC) is the second most common malignancy in the world and it accounts for 15% of female deaths due to cancer every year. Although hormonal therapy with tamoxifen (TAM) is a commonly used treatment for the disease, a recurring problem is that tumours eventually develop resistance to the drug. We are interested in investigating the role of FAM84B in BC tumorigenesis and the development of TAM resistance in these tumours. FAM84B has been shown to have higher expression in esophageal squamous cell carcinoma than in normal tissue and the protein was associated with increased tumour growth. Similar studies in prostate cancer have shown that FAM84B is associated with progression of the disease. The results of our analyses suggest that FAM84B may have a possible role in promoting events associated with enhancing the viability of MCF7 cells, leading to increased rates of growth and division. In addition, FAM84B may also function to direct events associated with the early developmental stages of BC. We did not, however, observe any impact of altered FAM84B expression on the development of TAM resistance in BC. Further research involving improved in vitro and in vivo studies, along with an examination of FAM84B’s impact on various oncogenic molecular signalling pathways, will help improve our understanding of the protein’s role in BC tumorigenesis.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/25005 |
| Date | January 2019 |
| Creators | Ramkairsingh, Marc |
| Contributors | Tang, Damu, Medical Sciences |
| Source Sets | McMaster University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis |
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