ErbB2 and Control of Growth in Breast Cancer Cells

Institution: University of California, San Diego
Investigator(s): Deborah Cadena, Ph.D. -
Award Cycle: 1995 (Cycle I) Grant #: 1KB-0140 Award: $144,936
Award Type: New Investigator Awards
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Initial Award Abstract (1995)
In order to address the important health issues surrounding the detection, diagnosis and prevention of breast cancer, it is important to understand the fundamental mechanisms of growth control in normal and malignant breast tissue. In approximately 30% of human breast cancers, a protein called erbB2 is present at levels significantly above those found in normal cells. Breast cancer tumors which involve these larger amounts of erbB2 protein are correlated with very aggressive cancer. The experiments proposed in this grant are intended to understand how the erbB2 protein carries out its job in normal and malignant growth of breast cells. Ultimately, these results could lead to novel preventative approaches which could decrease the morbidity and mortality of breast cancer.

The erbB2 protein is a member of a very important group of proteins called receptor tyrosine kinases. These receptors sit on the outer surface of cells where they wait to receive messages that are transported through the blood stream from other cells in the body. Such messages include hormones, such as insulin and growth factors. When these receptors receive the appropriate message, they pass information to the inside of the cell by using an enzyme activity called tyrosine kinase. The tyrosine kinase family of enzymes serve extremely important functions by passing information inside cells, termed signal transduction, and are key regulators of cell growth. Because of this important function in regulating when cells grow, these receptor tyrosine kinases can contribute to cancer if their activity is abnormal.

In order to understand the relationship of erbB2 to breast cancer, it is important to understand the fundamental mechanisms underlying signal transduction by the receptor. It is proposed that proteins that directly interact with erbB2 will function in important signaling mechanisms. Using molecular biology techniques, molecules will be identified that interact with specific parts of erbB2. The importance of these molecules will be determined by studying a human mammary cell line. Certain cell lines have characteristics of cancer cells. The newly identified molecules will be tested to see if parts of the molecule can actually alter these breast cancer cells. This result would strongly indicate that the molecule performs an important signaling function in breast cells. By analyzing the way that erbB2 carries out its function in breast cells, it is possible that new strategies of preventing the progression of certain breast cancers may be developed.

Final Report (1999)
In a large percentage of human breast cancers, a protein called ErbB2 and the closely related protein epidermal growth factor (EGF) receptor are present in significantly higher amounts than found in normal cells and are correlated with very aggressive growth properties. Experiments were proposed to identify and characterize proteins that allow the ErbB2 and EGF receptors to function in breast cells. Two regulatory genes, termed Snx1 and MLD, were isolated and their products characterized. We found that these proteins determine the amount of growth factor receptors in the cell. Thus, these studies may provide insight into new approaches to treat aggressive forms of breast cancer.

One of the regulatory proteins, Snx1, was isolated and directly interacts with the EGF receptor. Snx1, for sorting nexin 1, was found to specifically decrease the amount of EGF receptor in cells. The finding of Snx1 that can decrease the amount of EGF receptor protein could potentially have future therapeutic value in the treatment of human breast cancers (approximately 25-30%) that express this receptor. A second closely related gene, termed Snx2, was isolated from a human mammary library and also has potential for regulating levels receptors that may be involved in breast cancer. During this project we found another protein, termed MLD, that interacts with both ErbB2 and EGF receptor. When MLD was expressed at above normal levels, it caused decreased expression of EGF receptor. MLD is a new member of the membrane fatty acid desaturase gene family and is likely the d6 fatty acid desaturase. The d6 desaturase is an important enzyme n the metabolism of polyunsaturated fatty acids. This is important for breast cancer, since it has been shown that breast cancer rates differ between groups of women that consume different types of polyunsaturated fats.

Both the ErbB2 and EGF receptors, which are closely related members of the same protein family, have been implicated in the aggressiveness and responsiveness to drug therapies of certain human breast cancers. Identification of new regulatory proteins, such as Snx1 and MLD, offers the possibility of developing new strategies for preventing the progression of certain breast cancers.

The product of the MLD gene is a member of the membrane fatty acid desaturase family: overexpression of MLD inhibits EGF receptor biosynthesis
Index Medicus: Biochemistry
Authors: Cadena DC, Kurtin RC, Gill GN
Yr: 1997 Vol: 36 Nbr: 23 Abs: Pg:6960-70

A new member of the membrane fatty acid desaturase gene family, MLD alters EGF receptor expression
Periodical:Molecular Biology of the Cell
Index Medicus: Mol Biol Cell
Authors: Cadena DC, Kurtin RC, and Gill GN
Yr: 1996 Vol: 7 Nbr: Abs: 432a Pg: