Crosstalk between adipocytes and breast cancer cells with ESR mutations via adipsin enhances tumor growth.
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Issue Date
2023-08
Authors
Belyakov, Artem '23
Degree
Advisor
Jin, Kideok
Committee Members
Dearborn, Richard E.
Yager, Eric
Yager, Eric
Journal Title
Journal ISSN
Volume Title
Abstract
Estrogen receptor positive breast cancer is a prevalent disease traditionally treated with hormone therapy which relies on the expression of the estrogen receptor to starve the tumor of growth signaling due to estradiol. While hormone therapy generally has great outcomes, the development of endocrine resistance remains a huge hurdle, with poorer outcomes and less effective therapeutic options. Endocrine resistant tumors have been found to uniquely contain point mutations in the ligand binding domain of the Estrogen Receptor 1 (ESR1) coding region, predominantly Y537S and D538G. A growing body of literature has shown the stromal involvement in tumorigenesis, which supports resistance, survival, proliferation and eventual metastasis. Adipocytes have been found to promote breast cancer growth and invasion in coculture but without an understood mechanism. The complement system is generally associated with innate immunity but is increasingly found to promote tumor growth by dysregulation of inflammatory pathways. Since Adipsin (also known as Complement Factor D) is preferentially expressed in adipocytes, an investigation was done on the role of complement, specifically the C3a-Adipsin-C3aR axis on the impact of breast cancer cell characteristics. Using RT-qPCR and ELISA, it was found that C3a and Adipsin are both upregulated preferentially in the mutant cells as compared to wild type when cultured in adipocyte condition media. In addition, experimental inhibition of C3aR using the small molecule SB290157, had tumor attenuating effects that were limited to the mutated breast cancer cell lines. Using CyQuant for cell viability, and flow cytometry to investigate apoptosis, cell proliferation and cell cycle analysis, it was found that SB290157 had a drastic effect by decreasing cell viability and cell proliferation, increasing apoptosis, and causing cell cycle arrest at G2/M. Using knockdown of C3 and Adipsin by siRNA for the more sensitive mutant YS led to a marked decrease in cell viability as well. These findings contribute to the idea that endocrine resistant breast cancers are utilizing complement inflammatory pathways as one of their strategies to survive, proliferate and invade. As this pathway is investigated more, it may be possible to therapeutically block it for better breast cancer outcomes.
Citation
Belyakov A. Crosstalk between adipocytes and breast cancer cells with ESR mutations via adipsin enhances tumor growth. Ann Arbor (MI): Proquest LLC; 2023. 36 p.
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