FBXL16 as a novel factor in promoting endocrine therapy resistance and metastasis of ER+ breast cancer - Project summary Endocrine therapy (ET) resistance and metastasis are major obstacles for curing patients with advanced ERα+ breast cancer (ER+ BC). Upregulated oncogenic ERα activity plays critical role in advanced progression of ER+ BC. One essential mechanism of regulating ERα signaling is the ubiquitination- dependent proteasomal degradation of ERα and its co-activators such as steroid receptor coactivator 3 (SRC-3, also known as amplified in breast cancer 1). Owing to its direct effect of targeting ERα for degradation, fulvestrant is the only FDA-approved selective estrogen receptor degrader (SERD) as a first line endocrine agent for metastatic and locally advanced breast cancer and a second line drug for advanced metastatic breast cancer that has progressed after tamoxifen or aromatase inhibitor treatment. Unfortunately, either de novo or acquired resistance to fulvestrant occurs in the majority of the patients with advanced ER+ BCs. The molecular mechanism underlying fulvestrant resistance is still largely unknown. The proposed study aims to test an intriguing hypothesis that the F-Box protein FBXL16 stimulates oncogenic ERα activity by upregulating the stability and expression levels of ERα and coactivator SRC-3, thereby promoting breast cancer development, metastatic progression and endocrine therapy (ET) resistance. Two specific aims will be performed. Aim 1 is to determine the roles of FBXL16 in regulating the stability and expression levels of ERα and ERα LBD mutants; Aim 2 is to determine the role of FBXL16 in ER+ breast tumor growth, metastasis and endocrine therapy resistance. By conducting a variety of both in vitro and cell-based assays and in vivo tumor mouse model experiments, we expect to elucidate how FBXL16 upregulates the protein stability of ERα and ERα-LBD mutants and to determine the roles of FBXL16 in breast tumor development, metastasis and ET resistance. Our ultimate goal is to define FXBL16 as a new prognostic marker and/or a therapeutic drug target for treating advanced ER+ BCs, particularly in the patients with either de novo or acquired resistance to SERDs including those with ERα LBD activating mutations.
