Doctor of Philosophy (PhD)
Genetics, Cell Biology & Anatomy
Dr. Vimla Band
Breast cancer is a heterogeneous disease that is the second leading cause of cancer related deaths in women. Cancer is defined as abnormally heightened proliferation. In order for gene transcription and eventual translation to occur to drive the cell cycle to generate more cells, DNA must be uncoiled from nucleosomes by histone acetylation complexes. One of the key evolutionarily conserved components of these HAT complexes is alteration/deficiency in activation 3 (ADA3). In addition to the role in histone acetylation, this protein also functions as a coactivator for nuclear hormone receptors. Recent findings indicated that nuclear Ada3 correlates with ER+ breast cancers and a favorable survival, while cytoplasmic (overexpression) Ada3 correlates with ErbB2+ and EGFR+ breast cancers and a poor survival.
My thesis work focused on the role of Ada3 knockdown and overexpression on cellular proliferation in human derived cell lines. We showed knockdown of ADA3 in immortal hMECs led to inhibition of cell cycle progression, decrease in cyclin B, c-myc or H3K56 levels, and increase in p27 protein. In contrast, ADA3 overexpression in two immortal hMECs and two ER+ breast cancer cell lines enhanced proliferation. Cell cycle analyses showed increased cyclin B and decreased p27 upon ADA3 overexpression. Decreased p27 levels were due to increased turnover of p27 protein. Furthermore, ADA3 overexpression led to increased mRNA levels of early response genes c-fos, EGR1, and c-myc. Analysis of a large cohort of ER+ breast cancer tissue specimens showed a subset of ER+ tumors express higher levels of ADA3 and these tumors also express higher levels of c-myc (p
Griffin, Nicolas I., "The Role of ADA3 Overexpression in Proliferation Through Enhancing MYC Expression" (2016). Theses & Dissertations. 108.