Accession Number:

ADA371248

Title:

Transforming Growth Factor-B Receptors in Human Breast Cancer

Descriptive Note:

Annual rept. 1 May 98-30 Apr 99

Corporate Author:

YALE UNIV NEW HAVEN CT

Personal Author(s):

Report Date:

1999-05-01

Pagination or Media Count:

60.0

Abstract:

Transforming Growth Factor-B TGFBeta is the most potent known inhibitor of cell cycle progression of normal mammary epithelial cells. In general, advanced breast cancers are refractory to TGFBeta-mediated growth inhibition. The TGFBeta type I and -II receptors TBetaR-I and -II are the primary transducer of TGFBetas growth inhibitory effect. It is our working hypothesis that TGFBeta-resistance is caused by molecular lesions in the TBetaR genes. We first asked whether or not molecular lesions of the TGFBeta receptor genes are involved in the origin andor progression of breast cancer. Our findings indicate that a specific somatic mutation within the kinase domain of the TBetaR-I receptor S387Y occurs in primary breast cancers, and, more commonly, in lymph node metastases. This is the first example of a missense mutation in this gene in human malignancy. Secondly, we demonstrated that the S387Y mutation has a negative impact on the ability of the TBetaR-I receptor to transduce the TGFBeta signal. Finally, we have shown that allelic losses of both the TBetaR-I and -II genes occur in subpopulations of cells contained within primary breast carcinomas, suggesting that TGFBeta-refractory clones are selected for during breast cancer progression.

Subject Categories:

  • Biochemistry
  • Genetic Engineering and Molecular Biology
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE