Publication Date
2022
Document Type
Dissertation
Committee Members
Weiwen Long, Ph.D. (Advisor); Madhavi Kadakia, Ph.D. (Committee Member); David R. Ladle, Ph.D. (Committee Member); Hongmei Ren, Ph.D. (Committee Member); Shulin Ju, Ph.D. (Committee Member)
Degree Name
Doctor of Philosophy (PhD)
Abstract
Breast cancer is the most prevalent cancer in women. Approximately 75% of breast cancers are estrogen receptor alpha positive (ER+) and are treatable with endocrine therapies and/or CDK inhibitors. However, endocrine therapy (ET) resistance and metastasis are major obstacles in advanced ERα+ breast cancer (ER+ BCa) therapeutics. Upregulated oncogenic ERα activity plays critical role in progression of ER+ BCa. One essential mechanism of regulating ERα signaling is the ubiquitination-dependent proteasomal degradation of ERα. Owing to its direct effect on ERα degradation, fulvestrant is a first-line FDA-approved ET for metastatic and locally advanced breast cancer and a second-line drug for treatment of unresponsive ER+ BCa progression. Unfortunately, intrinsic or acquired resistance to fulvestrant develops in majority of patients with advanced ER+ BCa. The mechanism underlying fulvestrant resistance is still largely unknown. In the current study, we have identified F-Box and Leucine-Rich Repeat Protein 16 (FBXL16) as a novel positive regulator of oncogenic ERα signaling. F-box proteins are major components of the SCF (SKP1-CUL1-F-box) E3 ubiquitin ligases that mediate protein ubiquitination. FBXL16 does not show detectable interaction with CUL1 and is a poorly studied F-box protein. Our lab has recently discovered that FBXL16 upregulates several oncoproteins targeted by SCF-E3 ligases, including c-myc and β-catenin. However, little is known about the roles of FBXL16 in cancer. By data-mining of cancer-related databases and immunohistological analysis of BCa tissue microarrays, we found that FBXL16 is highly upregulated in invasive ductal and lobular carcinomas. There is a strong positive correlation between FBXL16 expression and ERα status, implying its important role in ER+ BCa. Our study reveals that FBXL16 stabilizes ERα and decreases ERα ubiquitination thereby promoting ERα-mediated transcription and breast cancer cell proliferation. Specifically, we identified that FBXL16 decreases estradiol-induced ERα degradation by antagonizing an E3-ubiquitin ligase, FBXO45. Moreover, FBXL16 silencing downregulates protein stability of constitutively active mutant ERα-Y537S and restricts proliferation of cells expressing ERα-Y537S. Silencing of FBXL16 accelerates fulvestrant-mediated ERα degradation and increases fulvestrant efficacy in inhibiting cell growth. In conclusion, our findings identify FBXL16 as a novel regulator of ERα signaling and a potential therapeutic target for treating advanced ER+ BCa.
Page Count
159
Department or Program
Biomedical Sciences
Year Degree Awarded
2022
Copyright
Copyright 2022, all rights reserved. My ETD will be available under the "Fair Use" terms of copyright law.
ORCID ID
0000-0002-7908-6462
