Novel Genes in Mammary Gland Development and Cancer

Institution: University of California, San Francisco
Investigator(s): Euan Slorach, Ph.D. -
Award Cycle: 2003 (Cycle IX) Grant #: 9FB-0155 Award: $80,000
Award Type: Postdoctoral Fellowship
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Initial Award Abstract (2003)
All cancers are ultimately the result of deregulated gene expression within cells of the body. The initial causative agents of this deregulation can be numerous and include environmental factors, inherited genetic factors, viral infections and damage to the immune system. However, irrespective of the source of the causative agent, it is the consequence of deregulated gene expression that leads to the unrestricted cell proliferation that ultimately forms a tumor.

Normally, the body regulates gene expression through a wide variety of control mechanisms, such as growth factor signaling, where signals from outside the cell are transmitted to the inside and lead to changes in gene expression. It is no surprise therefore that the genes regulating these pathways have been identified as being involved in cancer. One other way in which a cell regulates gene expression is through the activity of proteins known as transcriptional regulators. These proteins bind to DNA within the control region of genes, and alter the level of gene activity by regulating the rate at which the gene product (proteins) are made. A great deal of research has shown that changes in activity of these regulators are involved in a large number of different cancers.

Recently, a novel gene was identified in the fruit fly that would seem to code for a transcriptional repressors. We have identified in our lab, two highly similar genes that are present in the mouse (Melb1 and Melb2) and are also present in humans. Initial experiments in this lab have shown that these genes are both expressed at the site of breast formation in mice during embryonic development. These genes are expressed at a very early stage, and represent two of the earliest known genes expressed in the developing breast. Further studies in this lab have shown that the expression of these genes is dramatically altered in breast cancer compared to that of the normal breast tissue. Changes in levels of Melb1 gene expression in particular have been shown in breast tumors in both mice and humans. This project aims to determine the function of the proteins encoded by the Melb1 gene, and the consequences of altered gene expression in breast cancer. I will use both mouse models and human cells to determine the consequences of altering the levels of expression of this gene.

The identification of genes involved in the development of breast cancer is a critical first step towards identifying new targets for therapeutic drug development. However, with genes that are transcriptional regulators such as the Melb genes, and are therefore responsible for the expression of other genes, it is important to determine the target genes that are regulated by Melb1. Therefore we shall identify the DNA sequences that Melb1 binds to, and what particular genes this effects. These results will lead to a greater understanding of breast biology and what goes wrong in breast cancer. This knowledge can then be used to help develop preventative and curative therapies.