Extracellular matrix regulation of PTHrP and PTH/PTHrP receptor in a humanbreast cancer cell line

It was previously reported that 8701-BC breast cancer cells express the gen e for parathyroid hormone-related peptide (PTHrP) and its cognate receptor (PTHrP-R), and release immunoreactive PTHrP in the extracellular medium; it nas also found that PTHrP, in turn, exerts a role on the proliferative and invasive behavior in vitro of the same cell line. On the other hand, evide nce has been produced that adhesion of 8701-BC cells onto different collage n substrates influences in various,ways a number of phenotypic expressions, such as cell growth, motility, invasion of reconstituted basement membrane and production of lytic enzymes of the extracellular matrix (ECM). In ligh t of these previous data, we have examined whether substrates of either rec onstituted basement membrane or representative collagen components of the b reast tumor stroma (type I, V and OF/LB) might (i) regulate the PTHrP promo ter usage and mRNA splicing patterns, (ii) modulate quantitatively the extr acellular release of immunoreactive PTHrP (iP-THrP), and (iii) affect the e xpression of PTHrP-R. The results obtained give evidence that (i) 8701-BC c ells are able to utilize different start sites and mRNA splicing patterns f or PTHrP transcription; (ii) 'structural' components of the stroma, such as collagens, are by themselves capable of controlling both the expression pa ttern of the PTHrP gene slid the extent of extracellular release of iPTHrP, and (iii) PTHrP-R espression can he up- or don regulated in response to th e ECM substrate present. These data demonstrate that PTHrP and PTHrP-R expr ession by 8701-BC neoplastic cells can be modulated by ECM molecules, indir ectly supporting the active participation of stromal collagen composition i n the regulation of PTHrP-controlled circuits which may play a role in carc inogenesis. (C) 1999 Federation of European Biochemical Societies.