Growth Factor Control of Breast Tumor Cell Proliferation

Institution: University of California, San Diego
Investigator(s): Richard Kurten, Ph.D. -
Award Cycle: 1995 (Cycle I) Grant #: 1FB-0314 Award: $35,000
Award Type: Postdoctoral Fellowship
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease



Initial Award Abstract (1995)
The normal cyclic renewal of breast tissues is accompanied by variations in epithelial cell proliferation that are regulated by steroid hormones and peptide growth factors which are produced elsewhere in the body. I recently discovered two new human genes involved in the action of epidermal growth factor (EGF), a regulator of cell proliferation in breast tissues. I propose to evaluate their potential utility as targets for controlling the growth of breast tumor cells in tissue culture. This research is intended to provide a new foundation on which to design strategies for preventing disease progression and for treating advanced breast cancer in women. The potential impact of the planned research would be to provide another line of defense against breast cancer. Epidermal growth factor (EGF) regulates cell proliferation by binding its receptor, a large protein spanning the thickness of the cell membrane. The receptor protein has several sections, each of which performs a different, but related function. On the outside of the cell is a section that binds to EGF. When that binding occurs, a section on the inside of the cell becomes active as an enzyme to catalyze reactions. This section of the receptor will be studied in this project because it regulates some protein interactions that precede cell division. The genes I isolated code for two proteins, corkii-1 and corkii-2, that bind the enzymatic section of the molecule and regulate its level of activity. In so doing, corkii-1 and corkii-2 appear capable of controlling the ability of the EGF receptor to transmit information deeper into the cell. Most importantly, by controlling catalytic efficiency, these molecules set the sensitivity of a cell to EGF and determine the rate at which the cell divides; cells that divide too rapidly form tumors.

I plan to measure the levels of corkii-1 and corkii-2 in normal and malignant cultured cells derived from human breast tissue to establish the relationship between their levels and cellular proliferation rates. In a second line of investigation, molecular approaches employing antisense DNA technology and transfer of synthetic genes will be used to change the level of corkii-1 and corkii-2 in cultured breast tumor cells. The effects of these manipulations on proliferation of cultured breast tumor cells will serve as indicators of the potential utility of DNA-based drugs in slowing or eliminating tumor growth.


Final Report (1996)
Breast cancer is the result of uncontrolled cell proliferation in mammary gland tissues. The normal cyclic renewal of these tissues is accompanied by variations in epithelial cell proliferation that are regulated by steroid hormones and growth factors. I had previously identified two new human genes thought to be involved in the action of epidermal growth factor (EGF), a regulator of cell proliferation in breast tissues. I proposed to determine if the proteins encoded by these genes might provide novel targets for controlling the growth of tumor cells in tissue culture. During the course of this project, I discovered that one of these molecules, now called sorting nexin 1 (SNX1), could be used to control the number of EGF receptors on the surface of an individual cell. This was accomplished by using a synthetic gene for SNX1 to raise is concentration inside of the cell. As a result, these cells had fewer EGF receptors and were less able to turn on a marker gene associated with cell proliferation.

These findings have led me to propose that a synthetic SNX1 gene can be used as a DNA-based drug to slow or eliminate tumor growth. In the future, I will test this idea using transgenic mice. Transgenic mice have been genetically altered to make a particular protein in a selected tissue such as the mammary gland. Transgenic mice that make transforming growth factor alpha (TGF, another hormone that binds the EGF receptor) in their mammary glands always develop mammary tumors after 2 or 3 pregnancies. Using a synthetic SNX1 gene, these mice will be altered to make extra SNX1 in the mammary gland to determine if tumor development can be suppressed. If SNX1 does suppress TGF induced tumor formation in this animal model system, then one can begin to develop and test therapeutic strategies using SNX1 for women with breast cancer.

Identification of a second sorting nexin (SNX2) closely related to SNX1, a molecule that down regulates EGF receptors.
Periodical:Molecular Biology of the Cell
Index Medicus: Mol Biol Cell
Authors: Kurten RC, Leychkis Y, Gill GN
Yr: 1996 Vol: 7 (suppl) Nbr: Abs: 134a Pg:

A new member of the mnembrane fatty acid desaturase gene family, MLD, alters EGF receptor expression.
Periodical:Molecular Biology of the Cell
Index Medicus: Mol Biol Cell
Authors: Cadena DL, Kurten RC, Gill GN
Yr: 1996 Vol: 7 (suppl) Nbr: Abs: 134a Pg:

Enhanced degradation of EGF receptors by a sorting nexin, SNX-L
Periodical:Tumor Biology
Index Medicus:
Authors: Kurten RC, Cadena D, Gill GN,
Yr: 1996 Vol: Nbr: Abs: Pg:

Identification of proteins that bind to the tyrosine kinase domain of ERBB2
Periodical:FASEB Journal
Index Medicus: FASEB J
Authors: Cadena DL, Kurten RC, Wagner LE, Gill GN
Yr: 1995 Vol: 9 Nbr: 6 Abs: A1416 Pg: