TGF-Beta Resistance in Breast Cancer
Abstract
Transforming growth factor-Beta (TGF-Beta) potently inhibits cell proliferation by causing cell cycle arrest at the Gl phase. Smad proteins mediate the TGF-Beta antiproliferative responses by regulating the expression of several cell cycle components. We have recently discovered that Smad3, a key Smad protein for the TGF-Beta antiproliferative responses, is a major physiological substrate for cyclin-dependent kinases CDK4 and cDK2. Except for the Rb family members, Smad3 is the only cDK4 substrate demonstrated so far. CDK phosphorylation of Smad3 inhibits its transcriptional activity and antiproliferative function. Since cyclin Dl that activates CDK4 and the related cDK6 is amplified or overexpressed in a high percentage of human breast cancers, we examined whether Smad3 is highly phosphorylated by CDK in breast cancers. Using primary human breast cancer tissue microarrays and a phosphopeptide antibody against a CDK phosphorylation site in Smad3, we have found that overexpression of cyclin Dl in primary human breast cancer is strongly associated with immunohistochemical staining on the CDK phosphorylation site in Smad3. Thus, diminishing Smad3 activity by CDK phosphorylation may be an important mechanism for resistance to the growth-inhibitory effects of TGF-Beta in breast cancers.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2004
- Accession Number
- ADA429736
Entities
People
- Fang Liu
Organizations
- Rutgers University–New Brunswick