EPIDERMAL GROWTH-FACTOR AND AMPHIREGULIN UP-REGULATE MATRIX METALLOPROTEINASE-9 (MMP-9) IN HUMAN BREAST-CANCER CELLS

The EGF family of proteins encompasses several polypeptides such as ep idermal growth factor (EGF), transforming growth factor alpha (TGF alp ha), amphiregulin (AR) and heregulin (HRG-beta 1). These polypeptides regulate proliferation in breast cancer cells through interaction with membrane receptors. It has been previously shown that high EGF recept or number correlates with aggressive behavior and increased metastasis in human breast cancer. In the present study, we investigated the ass ociation between EGF and EGF-like ligand-induced DNA synthesis and sec retion of MMP-9 and MMP-2 in metastatic SKBR-3 and non-metastatic MCF- 7 breast cancer cells. Exposure of SKBR-3 cells to EGF or AR induces e xpression of MMP-9 but has no effect on MMP-2 secretion, In contrast t o EGF and AR, HRG had no effect on gelatinase induction. None of the E GF polypeptides had any effect on gelatinase induction in MCF-7 non-me tastatic breast cancer cells. While a relatively specific inhibitor of EGF receptor tyrosine kinase, PD 153035, inhibited EGF-, AR- and HRG- induced cell proliferation, it had no effect on MMP-9 induced by EGF a nd AR. Experimental evidence suggests that signaling mechanisms for ce ll proliferation and MMP-9 induction are mediated by different pathway s down-stream of EGF receptor autophosphorylation or that low levels o f EGF-induced signal that escape inhibition are sufficient to induce M MP-9 but unable to support cell proliferation. In addition, our result s suggest that EGF and AR may modulate invasion of metastatic breast c ancer cells by increasing the expression of MMPs. (C) 1997 Wiley-Liss, Inc.