Gene that Predicts Cancer Prognosis Maintains Differentiation of Mammary Ductal Cells

Zena Werb, Ph.D.
University of California, San Francisco
U01ES012801

A gene known as GATA-3 is in a family of genes responsible for driving the processes that take stem cells down the path of differentiation that lead to mature cells regardless of their ultimate fate. NIEHS-supported researchers at the University of California, San Francisco have now determined that GATA-3 is also required for the maintenance of differentiation in ductal cells of the mammary gland. Using laboratory mice genetically altered so that they lack GATA-3, the research team found that mature cells reverted to the less specialized undifferentiated state, which is a characteristic of aggressive cancer cells. The new finding suggests that the gene may play a key role in the development of breast cancer and possibly other malignancies.

Cancer researchers know that breast tumors with high GATA-3 expression have a good prognosis. The cancers tend to be well-differentiated and the cells maintain many characteristics of normal mammary cells including high numbers of estrogen receptors. On the contrary, cancers with low expression of the gene tend to be diffuse and poorly differentiated and lead to poor prognosis for the patient. The new research offers clues to why this is so.

Mammary ductal cells, also known as luminal cells, line the mammary ducts that carry milk during lactation. They are a primary site in the mammary gland for cancers to form. The research suggests that the loss of functioning genes and the subsequent failure to maintain the mature state of the cells is what leads to the loss of differentiation and uncontrollable proliferation during cancer progression. Prior to this finding, it was unclear that maintaining differentiation of mammary cells was an active process and that GATA-3 was responsible for the maintenance of mature cells. The researchers also found the GATA-3 protein in all luminal cells of mammary ducts in normal mice at puberty and into adulthood.

The UCSF research team is one of four centers that make up the Breast Cancer and the Environment Research Centers Program co-funded by NIEHS and the National Cancer Institute. The team is now focusing its efforts on how GATA-3 controls cell fate and its role in breast cancer. This research could also have implications in other cancer types.

Citation: Kouros-Mehr H, Slorach EM, Sternlicht MD, Werb Z. GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland. Cell. 2006 Dec 1;127(5):1041-55.