Therapeutic targeting of ATAD2 in endocrine-resistant breast cancer

Introduction: ATPase family AAA domain-containing protein 2 (ATAD2) is a highly conserved protein that functions as a coactivator of oncogenic transcription factors, and its bromodomain is critical for its association with acetylated chromatin. ATAD2 is frequently amplified in multiple types of cancer, including breast cancer. The upregulation of ATAD2 is often associated with poor patient outcomes and can be used as a prognostic marker. In breast cancer, ATAD2 is proposed to act as a coactivator of estrogen receptor (ER) alpha, which is selectively recruited upon estradiol stimulation, leading to the induction of a subset of ER target genes, including c-Myc, cyclin D1, and E2F1, which are required for breast cancer cell proliferation. Here, we examined the role of ATAD2 in hormone-resistant metastatic ER-positive breast cancers with activating mutations in ESR1, which currently have limited therapeutic options. Methods: We examined the expression of ATAD2 in human breast tumors and subtype-specific breast cancer cells, including endocrine therapy-resistant breast cancer cells. To investigate the therapeutic potential of ATAD2 in Y537S and D538G mutant breast cancer cells, we conducted genetic and pharmacological modulation of ATAD2 in endocrine-resistant breast cancer cells. Additionally, we established stable suppression of ATAD2 using shRNA in the Y537S mutant MCF-7 and T47D cells. We also performed a co-immunoprecipitation assay, which demonstrated an interaction between ATAD2 and ERalpha in Y537S MCF-7 cells. Results: Analysis of The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) data sets revealed elevated mRNA and protein levels of ATAD2 across all major subtypes compared with normal breast tissues. Additionally, ATAD2 was overexpressed in endocrine-resistant breast cancer cells, including Y537S palbociclib resistance and long-term estrogen-deprived (LTED) cell line models. Pharmacological and siRNA-mediated inhibition of ATAD2 significantly reduced the expression of ERalpha and its target genes in Y537S and D538G mutant breast cancer cells. More importantly, the inhibition of ATAD2 by a genetic or pharmacological agent potentially blocks ligand-dependent and ligand-independent ER signaling in endocrine-resistant breast cancer cells. Finally, our co-immunoprecipitation experiments showed that ERalpha directly interacts with ATAD2. Conclusion: Collectively, our study highlights that ATAD2 is necessary for ESR1 mutant signaling in endocrine-resistant breast cancer. Therefore, blocking ATAD2 is a promising therapeutic strategy for endocrine-resistant breast cancer, including ESR1 mutant breast cancer.