The primary cause of mortality in breast cancer is metastasis. Our research plan is focused primarily on the transcriptional lineage regulator factor, GATA3. The GATA3 gene is the third most mutated gene in breast cancer. GATA3 serves as a master regulator of breast epithelial luminal differentiation and maintenance and the GATA3 regulatory networks are deregulated during cancer progression. GATA3 status is an important prognostic factor in breast cancer. The loss of GATA3 plays an essential role in the loss of differentiation and the malignant conversion of breast cancer and the acquisition of metastatic capability. Well-differentiated tumors with high GATA3 expression have a lower propensity for metastasis, whereas poorly differentiated tumors with low GATA3 expression have a greater propensity for metastasis. Low GATA3 expression is strongly associated with higher histologic grade, positive lymph nodes, larger size, ER and PR negative status, and HER2 overexpression and a poorer prognosis. We have demonstrated that GATA3 is a suppressor of metastasis though its regulation of the differentiation state of the tumor cells as well as that of the tumor microenvironment. The goal of our research project is to define the molecular mechanisms through which the transcription factor GATA3 exerts its effects in regulating breast cancer metastasis.
In Specific Aim 1, we determine mechanisms regulating GATA3 expression. In our preliminary studies, we have identified Zeppo2 (Zpo2, ZNF503) and ZBTB32 as regulators of GATA3 expression. We will focus on their roles as inducers of mammary tumor differentiation, progression and metastasis. Although most breast tumors express GATA3, tumor cells with decreased GATA3 expression have a more undifferentiated, basal phenotype and a higher metastatic rate.
In Specific Aim 1, we will use chromatin immunoprecipitation followed by sequencing (ChIP-Seq) analysis to discover GATA3 targets in both mouse and human breast cancer. We will then investigate the mechanisms by which these GATA3-target genes contribute to GATA3's regulatory functions.
In Specific Aim 2, we will investigate how the transcriptional network regulating GATA3 expression, focusing on the ZNF503/Zeppo2 axis. Since GATA3 is a critical regulator of breast cancer differentiation and suppressor of metastasis, then understanding these functions in molecular detail could lead to biomarkers and new therapeutic approaches.

Public Health Relevance

Breast cancer is the most prevalent cancer in women and the second-most cause of cancer death, almost exclusively because of metastasis. Loss of GATA3 gene expression inhibits breast cell differentiation, induces the metastatic microenvironment and drives metastasis, resulting in a poor prognosis for patients. A fuller understanding of how GATA3 suppresses metastasis may lead to new breast cancer biomarkers and therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA190851-02
Application #
9102005
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Snyderwine, Elizabeth G
Project Start
2015-07-01
Project End
2020-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Gonzalez, Hugo; Robles, Isabella; Werb, Zena (2018) Innate and acquired immune surveillance in the postdissemination phase of metastasis. FEBS J 285:654-664
Gonzalez, Hugo; Hagerling, Catharina; Werb, Zena (2018) Roles of the immune system in cancer: from tumor initiation to metastatic progression. Genes Dev 32:1267-1284
Shahi, P; Wang, C-Y; Chou, J et al. (2017) GATA3 targets semaphorin 3B in mammary epithelial cells to suppress breast cancer progression and metastasis. Oncogene 36:5567-5575
Shahi, Payam; Wang, Chih-Yang; Lawson, Devon A et al. (2017) ZNF503/Zpo2 drives aggressive breast cancer progression by down-regulation of GATA3 expression. Proc Natl Acad Sci U S A 114:3169-3174