Appointment period: 1/1/2010 to 8/15/2010
Award: California Breast Cancer Research Program (CBCRP) Postdoctoral Fellowship #16FB-0075 entitled "The Role of ANCCA in Tamoxifen Resistant Breast Cancer"
The Role of ANCCA, a Nuclear Hormone Receptor Coregulator, in Estrogen-Independent Tumor Cell Proliferation and Tamoxifen Resistance
Selective estrogen receptor modulators (SERMS), such as tamoxifen (TAM), are the prevailing adjuvant treatment for the 70% of breast cancers that express estrogen receptor α (ERα). However, ERα-positive tumors generally acquire a TAM resistant phenotype over time, resulting in a very poor prognosis when the cancer recurs. Defining the mechanisms that confer TAM resistance will provide new breast cancer (BCa) targets and may restore the efficacy of TAM therapy. The Chen lab has identified ANCCA, an AAA+ protein, as an estrogen-regulated coactivator for ERα. Depletion of ANCCA results in strong inhibition of ER-positive BCa cell proliferation and downregulation of ERα target genes that play key roles in cell cycle progression. Our recent studies suggest a role for ANCCA in chromatin remodeling through recognition of acetylated histones and recruitment of histone acetyl- and methyltransferases. ANCCA also interacts with members of the E2F transcription factor family and plays a critical role in E2F recruitment to the Rb-E2F target genes in ER-negative BCa cells. These data suggest that ANCCA over-expression in breast tumors may promote cancer cell proliferation via stimulation of gene expression independent of ERα. This scenario may disrupt the antagonistic activity of TAM. Thus, I hypothesize that ANCCA over-expression in ER-positive tumors may promote tumor growth in the presence of anti-estrogens such as Tam.
To test this hypothesis I will first determine whether ANCCA over-expression promotes estrogen-independent proliferation and Tam-resistance of ER-positive BCa cells and xenograft tumors. Mechanistic studies will utilize microarray analyses to examine whether aberrant ANCCA promotes anti-estrogen resistance through reprogramming gene expression. Interestingly, a yeast ortholog of ANCCA called Yta7 may play a role in maintaining chromatin boundaries. Similarly, over-expressed ANCCA may establish new chromatin boundaries at specific gene loci that enable E2-independent growth and promote TAM resistance. To test this hypothesis, I will analyze at the genomic level the relationship of ANCCA occupancy and the change in heterochromatin and euchromatin boundaries between cells that are E2 sensitive and with relatively low levels of ANCCA and Tam-resistant cells with over-expressed ANCCA. Finally, the clinical relevance of ANCCA over-expression in BCa will be assessed through analysis of patient samples to determine if ANCCA levels correlate with disease progression.