Accession Number:

ADA454901

Title:

cSrc and Her2 Signaling Pathways Cooperate With Estrogen to Promote Estrogen Receptor Phosphorylation, Ubiquitination and Proteolysis in ER Negative Breast Cancers

Descriptive Note:

Annual summary rept. 27 Feb 2005-26 Feb 2006

Corporate Author:

MIAMI UNIV FL

Personal Author(s):

Report Date:

2006-03-01

Pagination or Media Count:

13.0

Abstract:

Estrogen regulates the proliferation and development of tissues expressing estrogen receptors and is implicated as a risk factor for the development of breast cancer. One third of new breast cancers do not express estrogen receptor ER protein and these have a worse prognosis than ER positive breast cancers. Here we investigated how mechanisms underlying the reduced ER protein in ER negative cancers may be linked to their aggressive behavior. Estrogen binding to the ER rapidly stimulates ubiquitin-dependent ER proteolysis which in turn regulates ER activity. Our data suggest that Src activates ER proteolysis. Src can phosphorylated ER in vitro. Src transfection accelerated ER proteolysis in MCF-7 cells. The Src inhibitor, PP1, impaired estrogen stimulated ER ubiquitylation and proteolysis in vivo and in vitro. The weakly ER positive, MDA-MB361 and ER negative, BT-20 breast cancer lines both have highly activated Src and decreased ER half-life. Thus, these data provide a direct link between Src activation and ER proteasomal degradation and supports a model whereby Src many phosphorylate ER, resulting in increased ubiquitination and proteolysis.

Subject Categories:

  • Biochemistry
  • Anatomy and Physiology

Distribution Statement:

APPROVED FOR PUBLIC RELEASE