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Abstract:
Cancer develops through accumulation of multiple genetic mutations. Loss of tumor suppressor gene p53 and activation of oncogene Neu/ErbB2 are among the most frequent genetic alterations in human breast cancer. We performed a retroviral insertional mutagenesis screen to identify genes that may contribute to mammary tumor formation in conjunction with deregulated p53 or Neu. Multiple proviral insertions from independent tumors were identified to be located within introns of the F-box gene Fbw4, suggesting that the structural alteration at this locus may provide selective growth advantage. The viral integrations result in marked overexpression of a novel, naturally occurring Fbw4 short isoform, which is also spontaneously enriched in several mouse and human breast cancer cell lines but not in non-transformed mammary epithelial cells, thus appears to be associated with malignant transformation. Overexpression of this short isoform in the normal mouse mammary epithelial cell leads to anchorage-independent growth in soft agar. Taken together, these observations indicate that aberrant expression of the short Fbw4 isoform observed in MMTV-induced tumors and spontaneous breast cancer cell lines may contribute to mammary tumorigenesis.
| Limitations: |
 APPROVED FOR PUBLIC RELEASE |
| Description: |
Annual summary rept. 15 Aug 2002-14 Jul 2005 |
| Pages: |
16 |
| Report Date: |
AUG 2005 |
| Contract Number: |
DAMD170210402 |
| Report Number: |
A423244 |
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