Interactions between progestins and heregulin (HRG) signaling pathways: HRG acts as mediator of progestins proliferative effects in mouse mammary adenocarcinomas

The present study addressed links between progestin and heregulin (HRG) sig naling pathways in mammary tumors. An experimental model of hormonal carcin ogenesis, in which the synthetic progestin medroxyprogesterone acetate (MPA ) induced mammary adenocarcinomas in female Balb/c mice, was used. MPA indu ced an in vivo up-regulation of HRG mRNA expression in progestin-dependent (HD) tumor lines. Mammary tumor progression to a progestin-independent (HI) phenotype was accompanied by a high constitutive expression of HRG. The HR G message arose from the tumor epithelial cells. Primary cultures of malign ant epithelial cells from a HD tumor line were used to investigate HRG invo lvement on cell proliferation. HRG induced a potent proliferative effect on these cells and potentiated MPA mitogenic effects. Blocking endogenous HRG synthesis by antisense oligodeoxynucleotides (ASODNs) to HRG mRNA inhibite d MPA-induced cell growth, indicating that HRG acts as a mediator of MPA-in duced growth. High levels of ErbB-2 and ErbB-3 expression and low ErbB-4 le vels mere found in HD cells. Treatment of these cells with either MPA or HR G resulted in tyrosine phosphorylation of both ErbB-2 and ErbB-3. Furthermo re, both HRG and MPA proliferative effects mere abolished when cells were t reated with ASODNs to ErbB-2 mRNA, providing evidence for a critical role o f ErbB-2 in HRG-induced growth. Finally, blocking type I insulin-like growt h factor receptor (IGF-IR) expression with ASODN resulted in the complete i nhibition of HRG proliferative effect, demonstrating that a functional IGF- IR is required for HRG mitogenic activity. These results provide the first evidence of interactions between progestins and HRB/ErbB signal transductio n pathways in mammary cancer and the first demonstration that IGF-IR is req uired for HRG proliferative effects.