REGULATION OF TISSUE-DEGRADING FACTORS AND IN-VITRO INVASIVENESS IN PROGRESSION OF BREAST-CANCER CELLS

Hormone-independent growth and invasiveness represent phenotypic prope rties acquired during early progression of breast cancer. We compared human mammary adenocarcinoma cells, MCF-7, which are estrogen-dependen t and poorly metastatic, with the estrogen-independent and highly meta static subline, MCF7/LCC1, with regard to expression of tissue-degradi ng factors of the matrix metalloproteinase (MMP)- and urokinase (uPA)- dependent degradative pathways, as well as for their in vitro invasive properties, Both cell lines showed low constitutive mRNA expression o f the MMP inhibitor TIMP-1. Baseline expression of TIMP-2 mRNA was als o very low in MCF-7 cells, whereas the MCF7/LCC1 level was much higher (similar to 10-fold). Furthermore, both cell lines revealed low const itutive capacity to migrate in an in vitro invasion assay. Treatment w ith 12-O-tetradecanoylphorbol-13-acetate (TPA; 100 nM) induced the mRN As for TIMP-1. as well as for MMP-1, MMP-9, the uPA receptor, and the uPA inhibitor PAI-1, amongst which only the responses of MMP-9 and PAI -1 were cell-specific. The mRNA levels of MMP-9 and PAI-1 were similar to 10-fold and similar to 15-fold higher in MCF7/LCC1 cells compared to MCF-7 cells. The secretion of immunoreactive PAI-1 was considerably elevated (> 20-fold) in TPA-treated MCF7/LCC1 cells, whereas the TPA- dependent level of 92-kDa MMP-9 was only similar to 2-fold higher in M CF7/LCC1 cells than in MCF-7 cells, In both cell lines treatment with TPA was associated with an increase (similar to 10-fold) in in vitro m igration, which. in the MCF7/LCC1 cells was significantly attenuated b y a reconstituted basement membrane extract (Matrigel). These data sug gest that TPA-responsive in vitro invasive properties that are probabl y associated with PAI-1 expression may co-vary with progression from h ormone-dependent to -independent breast cancer. (C) 1998 Lippincott-Ra ven Publishers.