Date of Graduation


Document Type

Dissertation (PhD)

Program Affiliation

Genes and Development

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Michelle C. Barton, PhD

Committee Member

Pierre McCrea, PhD

Committee Member

Sendurai Mani, PhD

Committee Member

Xiaobing Shi, PhD

Committee Member

Jianping Jin, PhD


In this dissertation, I report the oncogenic functions of an epigenetic regulator Tripartite Motif Protein 24 (TRIM24) coupled with metabolic reprogramming and epithelial mesenchymal transition (EMT) in breast cancer. TRIM24 was first established by our laboratory as a previously unknown negative regulator of p53 via its RING domain, as a co-regulator of nuclear receptors and a PHD/Bromodomain reader of specific histone modifications. TRIM24 expression correlates with poor prognosis of breast cancer, but the mechanisms of TRIM24-mediated oncogenesis are unknown. In the first part of my thesis, I found that TRIM24 is aberrantly expressed in early stages of breast cancer progression. Ectopic expression of TRIM24 induces malignant transformation of immortalized human mammary epithelial cells (TRIM24-iHMECs) and efficient growth of intermediate to high-grade xenograft tumors.

TRIM24 induces gross metabolic changes in the iHMECs with increased glycolysis and TCA cycle along with glucose uptake. TRIM24 causes deregulation of c-Myc and p53, the two key players that regulate cancer metabolism. TRIM24 is directly recruited to the promoters of several metabolic genes such as GLUT1, IDH1, IDH2 and c-Myc. Our hypothesis is that direct activation of various glucose metabolism genes by TRIM24 coupled with deregulation of key players of metabolism is critical for TRIM24-mediated oncogenic transformation in breast cancer.

TRIM24 is over-expressed in several cancers; however, a detailed analysis of how TRIM24 promotes tumorigenesis with progression to metastasis has not been elucidated. Prior to the metastatic progression of a tumor, cancer cells undergo a transition from an epithelial to a mesenchymal phenotype; termed as epithelial-mesenchymal transition (EMT). In the second part of my thesis, I found that TRIM24 is a driver of EMT in breast epithelial cells.

Upon TRIM24 over-expression in MCF10A cells, a mesenchymal-like change in the cellular morphology was observed. TRIM24-MCF10A cells exhibited marked decrease of E-cadherin and acquisition of various mesenchymal markers such as N-cadherin, fibronectin and vimentin. Similarly, upon TRIM24-knockdown in mesenchymal cells MDA-MB-231 and MDA-MB-468, there is reversal of EMT gene signature. Gene expression analysis of TRIM24-OE MCF10A cells further confirmed that EMT was among the top pathways that were enriched. Additionally, TRIM24 may be involved in direct transcriptional regulation of EMT genes as suggested by TRIM24-ChIP analysis and the presence of Histone H3 – K23 acetylation (H3K23ac) signature, for which the TRIM24-Bromodomain acts as a histone reader, at several EMT genes in MDA-MB-468 cells. We propose that aberrant expression of TRIM24 impacts a network of transcription regulatory factors and pathways to induce EMT and cancer metastasis.

For effective reduction of cancer mortality, it is very critical to intervene in the critical transition of non-invasive ductal carcinoma to extremely lethal invasive breast cancer. Our preliminary analysis suggests that TRIM24 plays a critical role in mechanisms involving both primary and metastatic cancer. Future studies will be focused to develop a better understanding of molecular mechanisms of TRIM24’ oncogenic function and will pave the way for developing therapeutic opportunities by targeting TRIM24.


TRIM24, Breast cancer, Metabolic reprogramming, EMT



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