Breast cancer - Cyr61 is overexpressed, estrogen-inducible, and associatedwith more advanced disease

To identify genes involved in breast cancer, polymerase chain reaction-sele cted cDNA subtraction was utilized to construct a breast cancer-subtracted library. Differential screening of the library isolated the growth factor-i nducible immediate-early gene Cyr61, a secreted, cysteine-rich, heparin bin ding protein that promotes endothelial cell adhesion, migration, and neovas cularization, Northern analysis revealed that Cyr61 was expressed highly in the invasive breast cancer cell lines MDA-MB-231, T47D, and MDA-MB-157; ve ry low levels were found in the less tumorigenic MCF-7 and BT-20 breast can cer cells and barely detectable amounts were expressed in the normal breast cells, MCF-12A, Univariate analysis showed a significant or borderline sig nificant association between Cyr61 expression and stage, tumor size, lymph node positivity, age, and estrogen receptor levels. Interestingly, expressi on of Cyr61 mRNA increased 8- to 12-fold in MCF-12A and 3- to 5-fold in MCF -7 cells after 24 and 48-h exposure to estrogen, respectively. Induction of Cyr61 mRNA was blocked by tamoxifen and ICI182,780, inhibitors of the estr ogen receptor. Stable expression of Cyr61 cDNA under the regulation of a co nstitutive promoter in MCF-7 cells enhanced anchorage independent cell grow th in soft agar and significantly increased tumorigenicity and vascularizat ion of these tumors in nude mice. Moreover, overexpression of Cyr61 in MCF- 12A normal breast cells induced their tumor formation and vascularization i n nude mice. In summary, these results suggest that Cyr61 may play a role i n the progression of breast cancer and may be involved in estrogen-mediated tumor development.