GROWTH-HORMONES AND ONCOGENES IN MAMMARY ADENOCARCINOMAS INDUCED BY MEDROXYPROGESTERONE ACETATE IN BALB C MICE/

We have studied the involvement of growth factors (GF), their receptor s (GP-R) and oncogenes in modulating tumor growth in the medroxyproges terone acetate (MPA)-induced mammary tumor model in BALB/c mice. We de monstrated the presence of both ligands of the insulin-like growth fac tor family (IGF-I, IGF-II) and the two types of receptors (IGF-RI, IGF -RII). MPA upregulated IGF-II mRNA and protein levels in hormone-depen dent lines (MPA-D). The progression to a hormone-independent phenotype was accompanied by a high constitutive expression of IGF-II and by a significant decrease in IGF-IIR number. An antisense strategy used to evaluate the role of IGF in the MPA-induced growth of epithelial MPA-D cells showed that IGF mediate progestin-induced mammary tumor growth by autocrine/intracrine pathways. We also studied the role of hereguli ns (HRG), the recently identified ligands for the c-erbB3 and c-erbB4 oncogenes. HRG mRNA expression was restricted to tumors of ductal orig in. MPA induced an in vivo up-regulation of HRG expression. Finally, w e also found that MPA may be exerting its proliferative effect on MPA- D lines by inhibiting the expression of transforming growth factor pi, (TGF-PI) and the lack of expression of TGF-PI in hormone-independent tumors may be related to the acquisition of autonomous growth.