Oncogene Regulation in Mammary Cancer

Institution: The Burnham Institute for Medical Research
Investigator(s): Robert Oshima, Ph.D. -
Award Cycle: 1996 (Cycle II) Grant #: 2RB-0109 Award: $616,191
Award Type: Research Project Awards
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Initial Award Abstract (1996)
Breast cancer, like other types of cancer, is a genetic disease caused by the permanent changes of specific genes which result in unregulated growth of mammary gland cells. Progress in cancer and general biological research has identified a relatively large number of different genes which, when changed, can lead to the inappropriate growth of particular tissues. With the accumulation of one or multiple changes this abnormal growth develops into cancer. One of the most important discoveries of the last ten years has been the realization that many of these key individual genes act in different ways to transmit information from outside the cell through a chain of gene products and finally to the central nucleus where all the genetic information is stored. In the nucleus, these signals act through proteins called transcription factors to alter how much of our genetic information is read. In turn, the reading or transcription of multiple genes leads to the uncontrolled growth of cells and alterations in their behavior. The concept of a chain of different gene products which pass information to the nucleus has helped us to group and order the action of different gene products into pathways which act like a chain of command which passes information from one link in the pathway to the next. An inappropriate message to grow could be started at many points in the signal pathway.

The main idea of this proposal is to try to correct at the nucleus the inappropriate signals to grow instead of at the many different points upstream which may start the signal. The multiple different signals which the cell receives seem to funnel through a limited number of key nuclear proteins in the nucleus. We will inhibit the action of one of the these key proteins, the Ets transcription factors, by engineering a mouse which expresses an inhibitory form of Ets specifically in mammary glands. This mouse will then be mated to another type of mouse which always develops mammary tumors due to the growth signals started by a mutant protein at the cell surface. The effect of inhibiting the Ets transcription factors on the appearance and growth of the tumors can then be evaluated. This work may identify a key target for controlling the growth of breast cancer cells. If the Ets transcription factors are essential for the unregulated growth of breast cancer cells, it may be possible to design drugs which interfere with the action of these specific proteins. The advantage of identifying a nuclear target for intervention is that in theory, such a target may be effective for many different tumors that are started because of a variety of possible upstream alterations.

Final Report (1999)
We have evaluated the role of the Ets2 regulatory protein in experimental mammary. Two types of experiments were performed. First, we used mammary tumor cells in culture to evaluate the effect of expressing inhibitory forms of the Ets2 protein. These results were sufficiently encouraging to move to animal studies. Fourteen transgenic mouse strains were generated representing four basic genes. Expression of the test genes was measured in all of these animals but tissue specific expression in mammary gland was not found. In most animals, the gene was expressed in a wide variety of tissues but was particularly low in virgin mammary gland. Four of these mouse lines express elevated levels of forms of Ets2 in lung and spleen. These models may be valuable for lung cancer and immunological studies.

The major technical problem encountered was that the regulatory sequences used to drive expression of the various forms of Ets2 did not perform as expected. Subsequent to the beginning of this project, other investigators have confirmed the failure of these particular promoter constructions to reproduce earlier reporter tissue specific patterns. However, by using mice which have had a targeted mutation of the Ets2 gene, we found that decreasing the amount of the Ets2 by half resulted in much smaller mammary tumors.

The primary goal of evaluating the importance of Ets2 in mammary tumorgenesis was accomplished. These findings were published (Cancer Research 1999 Sep 1;59(17):4242-6. We now need to determine what other mammary tumor models are similarly limited by Ets2 and the mechanism by which tumor progression is slowed. It may lead to methods for evaluating whether patients may be predisposed to rapid or slow progression of breast cancer.

A Single Targeted Ets2 Allele Restricts Development of Mammary Tumors in Transgenic Mice
Periodical:Cancer Research
Index Medicus: Cancer Res
Authors: Neznanov N, Man A, Yamamoto H, Hauser C, Cardiff RD, and Oshima RG
Yr: 1999 Vol: 59 Nbr: 17 Abs: Pg:4242-4246