GATA-3 Expression in Hormone Responsive Breast Cancer

Institution: Stanford University
Investigator(s): Ronald Weigel, M.D., Ph.D. -
Award Cycle: 1999 (Cycle V) Grant #: 5JB-0047 Award: $232,444
Award Type: IDEAS II
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Initial Award Abstract (1999)
The female hormone, estrogen, plays an important role in normal breast development and in the development of breast cancer in women. For reasons that are not entirely clear, some cancers retain their ability to respond to estrogen. Under these conditions the anti-estrogen, tamoxifen, has been shown to reduce the growth and spread of these cancers. The ability of cancers to response to tamoxifen is related to the presence of a protein in the cancer cells known as estrogen receptor (ER). ER is a protein that is present inside the cell of some breast cancers and which controls the ability of that cell to grow in the presence of estrogen or stop growing in the presence of anti-estrogens such as tamoxifen. When patients are treated with tamoxifen for long periods of time, cancer cells will develop that no longer respond to tamoxifen. Many of these cancers still make ER, which leads us to conclude that something in addition to ER is necessary for tamoxifen to work in a clinical setting. We have recently found another protein called GATA-3, which is made in almost all breast cancers that make ER. We know from other studies that GATA-type proteins are able to bind to ER, thereby altering the function of these two proteins. Drugs such as tamoxifen can break apart GATA and ER thus allowing the GATA protein to turn on other genes in side the cell. Our novel finding, therefore, suggests a new mechanism of tamoxifen action and offers the possibility of understanding why some patientís tumors no longer respond to tamoxifen.

The experiments planned will allow us to understand what GATA-3 is doing in breast cancer cells and how tamoxifen alters the function of GATA-3. We know from other studies that GATA-3 turns other genes on inside cells. We will first define which genes are regulated by GATA-3 in a hormone responsive breast cancer cell line. Genes controlled by GATA-3 will be found by comparing genes that are turned on when GATA-3 is put into cells and by finding genes that are turned off when GATA-3 is eliminated. We will then determine if the genes controlled by GATA-3 can be turned on and off with the drug tamoxifen. We expect to show that the ability to switch genes on and off with tamoxifen or estrogen requires both ER and GATA-3 proteins. Ultimately, these experiments may provide a way to help us predict which women will be helped by tamoxifen treatment and may offer new approaches to treat women whose tumors become resistant to tamoxifen therapy.

Final Report (2001)
Patients who have breast cancers with estrogen receptor (ER) have an improved survival and are more likely to respond to hormonal therapy than patients with tumors that do not have the receptor. We have previously found an association between ER and another protein, GATA-3, in breast cancer. This grant proposal explores the mechanism and physiologic consequences of GATA-3 in breast cancer. The proposal has three aims: to identify GATA-3 target genes in breast cancer; to determine if GATA-3 regulated genes are hormone responsive, and; to correlate the presence of GATA-3 and GATA-3 target genes with clinical response in primary breast cancers.

We have examined interactions between ER and GATA-3 using several different approaches, and found no direct interaction between these two proteins. In order to determine how GATA-3 functions in breast cancer, we are attempting to identify target genes that are regulated by the GATA-3 transcription factor. We have engineered an adenovirus that expresses GATA-3, which will be used to infect GATA-3-negative breast cancer cells. This system will allowed an analysis of what genes are newly expressed when GATA-3 is introduced into the cells. Using cDNA microarrays, we identified a number of GATA-3 target genes including fms-related tyrosine kinase 1, a novel serine (or cysteine) proteinase inhibitor and cytokeratin 13. In order to determine if GATA-3 is involved in hormone response, we have examined the tumors from seven women that recurred during tamoxifen treatment. As was found in non-selected tumors, there was a striking correlation between ER and GATA-3 expression in tumors that recur on tamoxifen treatment. These results indicate that loss of GATA-3 does not appear to be a mechanism accounting for a lack of hormone response. Future directions of research will investigate the mechanism of GATA-3 gene regulation in hormone responsive breast cancer and will also determine the basis for the association between GATA-3 and ER.

Understanding basic mechanisms of hormone response will help to develop novel therapeutic approaches to the treatment of breast cancer. If the GATA-3 factor is involved in regulating hormone-response, this factor will be an important target to focus the design of new drug treatments.