GENISTEIN INHIBITS BOTH CONSTITUTIVE AND EGF-STIMULATED INVASION IN ER-NEGATIVE HUMAN BREAST-CARCINOMA CELL-LINES

Genistein, a natural flavone compound, has been proposed to be respons ible for the lower rate of breast cancer in Asian women. The cellular mechanisms of genistein's inhibition of breast cancer progression are largely unknown. In a previous study our laboratory has presented evid ence that genistein inhibits cell proliferation of breast carcinoma ce lls, an inhibition which is associated with a specific G2/M arrest ind uction of p21(WAF/CIP1) expression and apoptosis. In the present study , we present experimental evidence that illustrates that the actions o f genistein are not limited to anti-proliferation: we show that genist ein can inhibit both constitutive as well as epidermal growth factor ( EGF)-stimulated invasion in estrogen receptor (ER)-negative human brea st carcinoma lines, MDA-MB-231 and MDA-MB-468. This inhibition is char acterized by the down regulation of MMP-9 (92 kDa type IV collagenase) and up regulation of TIMP-1 (tissue inhibitor of metalloproteinases) and the trypsin inhibitors: protease nexin-II (PN-II) and alpha 1-anti trypsin (alpha 1-AT). The in vivo actions of genistein may therefore e xtend beyond those traditionally implicated in chemoprevention, e.g., antiproliferation; genistein may act in vivo by blocking additional st ages of breast cancer progression such as those stages resulting in in vasion and metastasis.