An Investigation into the Role of 27-Hydroxycholesterol and Estrogen Receptors in Adipose Tissue, Obesity, and Breast Cancer

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ASGHARIKHONAKDARI-DISSERTATION-2021.pdf (31 MB)

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2021-05

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Abstract

Obesity is an emerging health crisis all over the world. With obesity comes several other health disorders such as type-2 diabetes, cardiovascular diseases, and cancers. Hence, understanding the underlying reasons for obesity is of paramount importance as it can guide us in developing new therapeutic approaches for preventing or decreasing the obesity rates. Breast cancer is the second cause of cancer-related deaths among women worldwide. Endocrine resistance in breast cancer which occurs after endocrine therapies, causes the tumors to relapse after years of dormancy. While estrogen receptors (ERs) mutations and malfunctions of other signaling pathways (e.g., MAPK signaling) are some of the underlying reasons for endocrine resistance in breast cancer, the underlying causes of 60% of endocrine resistance cases remain completely unknown. Estrogen and estrogen receptors play important roles in both obesity and breast cancer. 27-Hydroxycholesterol (27HC), the first identified endogenous selective estrogen receptor modulator, can modulate the activity of estrogen receptors in different tissues and thus can be one of the important factors in regulating the functions of ERs in the context of obesity and breast cancer. In this dissertation, I first showed that 27HC mostly works as an antagonist for ERs activity in different tissues. Next, I investigated the effects of 27HC on adipose tissues and obesity. My research showed that 27HC increases body weight gain in the presence of a high-fat, high- cholesterol diet in an ER-dependent manner. Moreover, 27HC increases body fat percentage regardless of the diet and affects adipose tissue gene expression and induces inflammation in the adipose tissue. I also showed that 27HC alters the morphology and function of brown adipose tissue. In regard to endocrine resistance in breast cancer, I showed that 27HC increases the growth rate of the endocrine-resistant breast cancer cells, and I also found a novel group of genes that can be the underlying reasons for the endocrine development and progression. All in all, the research presented in this dissertation confirms the importance of 27HC in obesity and breast cancer and opens new doors toward the development of potential therapeutics to decrease the obesity rates, as well as treatment of endocrine-resistant breast cancer.

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Obesity, Breast Cancer, Nuclear Receptors, Estrogen, 27-Hydroxycholesterol

Citation

Portions of this document appear in: Asghari, A.1 and Umetani, M.1,2, 2020. Obesity and Cancer: 27-Hydroxycholesterol, the Missing Link. International Journal of Molecular Sciences, 21(14), p.4822; and in: Asghari, A.1 And Umetani, M.1,2, 2020. ‘Estrogen Receptors and Obesity, with Focus on Adipose Tissues’, In Chen, G.G., Tong, M.C., van Hasselt, C.A., Estrogen Receptors: Structure, Functions and Clinical Aspects. Nova Science Publishers; and in: Asghari, A.1 and Umetani, M.1,2, 2020. Obesity and Cancer: 27-Hydroxycholesterol, the Missing Link. International Journal of Molecular Sciences, 21(14), p.4822; and in: Matsubayashi, M., Sakaguchi, Y.M., Sahara, Y., Nanaura, H., Kikuchi, S., Asghari, A.1, Bui, L., Kobashigawa, S., Nakanishi, M., Nagata, R. and Matsui, T.K., 2021. 27- Hydroxycholesterol regulates human SLC22A12 gene expression through estrogen receptor action. The FASEB Journal, 35(1), p.e21262; and in: Asghari, A., Ishikawa, T., Hiramitsu, S., Lee, W.R., Umetani, J., Bui, L., Korach, K.S. and Umetani, M., 2019. 27-Hydroxycholesterol promotes adiposity and mimics adipogenic diet-induced inflammatory signaling. Endocrinology, 160(10), pp.2485- 2494; and in: Asghari, A.1 And Umetani, M.1,2, 2020. ‘Estrogen Receptors and Obesity, with Focus on Adipose Tissues’, In Chen, G.G., Tong, M.C., van Hasselt, C.A., Estrogen Receptors: Structure, Functions and Clinical Aspects. Nova Science Publishers; and in: Asghari, A.1 and Umetani, M.1,2, 2020. Obesity and Cancer: 27-Hydroxycholesterol, the Missing Link. International Journal of Molecular Sciences, 21(14), p.4822; and in: Asghari, A.1, Wall, K., Gill, M., Del Vecchio, N., Allahbakhsh, F., Wu, J., Dang, N., Zheng, W. J., Wu, H., Umetani, M.1,2 and Maroufy, V., 2021. Dynamic Gene Expression Analysis Finds Novel Genes Causing Endocrine Resistance in Breast Cancer. Science, Submitted.

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https://hdl.handle.net/10657/10213

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