| Budget Amount *help |
¥14,700,000 (Direct Cost: ¥14,700,000)
Fiscal Year 2006: ¥7,100,000 (Direct Cost: ¥7,100,000)
Fiscal Year 2005: ¥7,600,000 (Direct Cost: ¥7,600,000)
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| Research Abstract |
Estrogen receptor alpha (ERα) is a valuable prognostic factor in early-stage breast cancer, however, ERα-negative cancers typically exhibit higher histological grades than ERα-positive cancers during the progressive stages. In contrast, TGF-β acts as a tumor suppressor early in tumor development, but promotes invasion and metastasis at later stages. We found that exogenous expression of ERα in ERα-negative breast cancer cells abrogated TGF-β-mediated signaling pathways, reducing the invasive and metastatic potential of these cells. ERα formed a protein complex with Smad, a signal transducer in the TGF-β pathway, and Smurfs, ubiquitin ligases, to induce their ubiquitination and subsequent degradation. In human breast tumor tissues, an anticorrelation between ERα and Smad protein levels was observed. These findings suggest that ERα, opposes the effects of TGF-13 on cancer progression via a novel non-genomic mechanism. Several other nuclear receptors (NRs) tested also possessed the ability to induce Smad degradation. These observations provide new insight into non-genomic functions of NRs and the mechanisms underlying NR-mediated suppression of tumor invasion.
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