Accession Number:

ADA386074

Title:

Altering Ets Activity to Reverse Transformation of Breast Cancer Cells

Descriptive Note:

Annual rept. 1 Jan-31 Dec 1999

Corporate Author:

BURNHAM INST LA JOLLA CA

Personal Author(s):

Report Date:

2000-01-01

Pagination or Media Count:

14.0

Abstract:

The Ets family of transcription factors are downstream targets of many signal transduction steps in tumor cells. Overexpression the DNA-binding domain of Ets2, which interferes with Ets-dependent transcription, inhibits Ras-mediated cellular transformation. We hypothesize that altering Ets activity might be an effective way to reverse the transformed phenotype of breast cancer cells. We analyzed the effect of stable expression of a variety of Ets2 constructs in RAS-transformed NIH-3T3 cells DT-3T3 and in a human breast cancer cell line MDA-MB-435. Overexpression of the dominant inhibitory mutant Ets2DBD lead to loss of anchorage independent growth in soft agar in both cell types. Unexpectedly, in DT-3T3 cells, high expression of Ets2 lead to reversion of transformation parameters like loss of anchorage independent growth, reorganization of stress fibers and reduced tumorigenicity in nude mice. An even stronger transcriptional activator, VPl6Ets2 increased the apparent reversion activity in these cells. In MDA-MB-435 cells, high levels of Ets2 seem to be toxic to these cells, but moderate amounts can also revert these cells to anchorage dependence. These results suggest that the balance of Ets factors is important for maintaining multiple aspects of the transformed phenotype of breast tumor cells, and are an appropriate target for intervention. The Ets family of transcription factors are downstream targets of many signal transduction steps in tumor cells. Overexpression the DNA-binding domain of Ets2, which interferes with Ets-dependent transcription, inhibits Ras-mediated cellular transformation. We hypothesize that altering Ets activity might be an effective way to reverse the transformed phenotype of breast cancer cells. We analyzed the effect of stable expression of a variety of Ets2 constructs in RAS-transformed NIH-3T3 cells DT-3T3 and in a human breast cancer cell line MDA- MB-435.

Subject Categories:

  • Genetic Engineering and Molecular Biology
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE