ANALYSIS OF THE PROLIFERATIVE RESPONSE TO LYSOPHOSPHATIDIC ACID IN PRIMARY CULTURES OF MAMMARY EPITHELIUM - DIFFERENCES BETWEEN NORMAL AND TUMOR-CELLS

The effect of lysophosphatidic acid (LPA) on the proliferation of norm al and tumor mouse mammary epithelial cells in primary, serum-free, co llagen gel cell culture was evaluated. LPA stimulated the growth of no rmal mammary epithelial cells from mature virgin mice. The growth of p regnancy-dependent tumors (PDT) was generally stimulated, although the response was attenuated in some of these tumors compared to normal ce lls. In contrast, the growth of 70% of ovarian-independent tumors (OIT ) was inhibited by LPA; the remainder were unaffected. LPA stimulated cAMP accumulation and phosphoinositide (PI) hydrolysis in normal, PDT, and OIT. Thus, the regulation of adenylyl cyclase and PI-specific pho spholipase C by LPA is similar in normal and tumor cells. Pertussis to xin (PT) partially inhibited LPA-stimulated growth in normal cells but did not affect LPA-stimulated PI hydrolysis or cAMP accumulation. Thu s, PT-sensitive and -insensitive proliferative pathways are activated. PT also inhibited LPA-stimulated growth of PDT but generally had no e ffect on the growth of OIT. These results show that the mitogenic resp onse to LPA is attenuated in the hormone-dependent phenotype and switc hes to growth inhibition in hormone-independent tumors. Furthermore, L PA stimulates multiple signal transduction pathways mediated by PT-sen sitive and -insensitive G proteins. The PT-sensitive pathways are not tightly coupled to the proliferative response to LPA in tumor cells. T hese data suggest that alterations in G protein function may occur dur ing tumor progression. (C) 1995 Academic Press, Inc.