Understanding the role of GATA3 in breast cancer
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Despite recent advances in our understanding of the mechanisms underlying the initiation and progression of breast cancer, patients who develop metastatic disease have poor prognoses. The focus of this project is to understand how GATA3, a transcription factor that is lost in breast cancer progression, functions at the molecular and cellular level. Decreased expression of GATA3 has been associated as a strong negative prognostic indicator. The Werb lab at UCSF has shown that in the normal mouse mammary gland, GATA3 maintains luminal epithelial cell differentiation, and deletion of GATA3 results in proliferation and detachment of the luminal epithelial cells from the basement membrane. In the pathologic situation, breast tumors may suppress GATA3 to promote proliferation and metastasis, but the molecular effects of losing GATA3 are not well understood. One possibility is that GATA3 regulates the expression of microRNAs (miRNAs), which are small, non-coding RNAs that serve to modulate gene expression by either inhibiting translation or causing degradation of the target mRNAs. Indeed, abnormal expression of miRNAs has been implicated in cancer biology as a general mechanism underlying many tumor-specific processes.
 
 
 
 
 
 
 
 In this dissertation project, the aims are to identify the miRNA targets controlled by GATA3 and determine the relationship of GATA3 and miRNA expression in tumor samples from mice and humans. These experiments are designed to determine whether expression of these miRNAs in GATA3-negative tumor cells is sufficient to prevent tumor spread. We plan to use a bioinformatics approach (i.e., the application of information technology to the field of molecular biology) to identify the mRNA targets of these miRNAs and validate these targets using in vitro assays. Our methods include PCR-based microRNA arrays to identify differentially expressed miRNA targets controlled by GATA3 and in mouse models of breast cancer. Next, actual tumor samples from both mice and humans will also be analyzed by immunohistochemistry and in situ hybridization to understand the relationship between GATA3 and miRNAs. Finally, we plan to conduct studies in mice using “knockdown” and over-expression approaches. Metastasis will be monitored in real-time by bioluminescent whole-animal imaging, and also by recovering and analyzing the tumors from mice at selected time points. 
 
 
 
 
 
 
 
 The underlying rationale for this project is the general appreciation that breast cancer cells may “hijack” normal, developmental regulatory pathways to promote proliferation and metastasis. Because loss of GATA3 correlates strongly with poor prognosis in humans, understanding the mechanisms by which GATA3 controls biological processes is critical to our understanding of breast cancer. In addition, because miRNAs also have the potential to be translated into therapeutics, investigating the link between GATA3 and miRNAs may provide valuable insight into both the basic biology underlying breast cancer and offer novel therapeutic strategies.