The Involvement of Human Cyr61 in Heregulin Induction of Breast Tumor Progression
Abstract
Cyr61, a member of the CCN gene family, was isolated and identified by differential expression between estrogen receptor (ER)-positive and ER-negative breast cancer cells. Cyr61 is a ligand for the integrin av-beta-3, which is involved in tumorigenesis and angiogenesis (formation of new blood vessels). We showed previously that expression of Cyr61 in HRG-transfected MCF-7 cells is greatly increased compared to parental MCF-7 cells. We also showed that Cyr61 is expressed in all the invasive, metastatic, HRG-expressing, and ER-negative breast cancer cell lines. Moreover, Cyr61 was detected in about 30% of invasive human breast tumor biopsies. Most significantly, an anti-Cyr61 blocking antibody abolishes the invasiveness and migration of HRG-expressing breast cancer cells in vitro. To understand the role of Cyr61 in breast cancer progression, the human Cyr61 cDNA was introduced to ER-negative, HRO-negative breast cancer cells. Cyr61-expressing cells showed a growth advantage in serum-depleted conditions. The preliminary results suggest that Cyr61 is sufficient to promote estrogen independence and anti-estrogen resistance of breast cancer cells both in vitro and in vivo. Cyr61-expressing breast cancer cells are invasive in vitro and tumorigenic in vivo. The mechanism involved in Cyr61-induced tumor formation and aggressiveness is mediated via specific activation of the MAPK and PI3K/AKT pathways. Blocking of Cyr61 expression in aggressive breast cancer cells by specific anti-sense oligonucleotides or by constitutive expression of anti-sense Cyr61 messages results in phenotypic reversion, including reacquisition of E2 requirement for growth and anti-E2 Sensitivity, in addition to reduced invasiveness and matrix protease activity in vitro, and decreased tumoriginecity. Taken together, these results strongly indicate that Cyr61 plays a critical role in breast cancer progression.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2001
- Accession Number
- ADA396431
Entities
People
- Miaw-sheue Tsai
Organizations
- University of California, Berkeley