Elizalde P V, Balaña M E, Charreau E H
Instituto de Biología y Medicina Experimental, Buenos Aires, Argentina.
Medicina (B Aires). 1997;57 Suppl 2:70-4.
We have studied the involvement of growth factors (GF), their receptors (GF-R) and oncogenes in modulating tumor growth in the medroxyprogesterone acetate (MPA)-induced mammary tumor model in BALB/c mice. We demonstrated the presence of both ligands of the insulin-like growth factor 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-dependent 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 heregulins (HRG), the recently identified ligands for the c-erbB3 and c-erbB4 oncogenes. HRG mRNA expression was restricted to tumors of ductal origin. MPA induced an in vivo up-regulation of HRG expression. Finally, we also found that MPA may be exerting its proliferative effect on MPA-D lines by inhibiting the expression of transforming growth factor beta 1, (TGF-beta 1) and the lack of expression of TGF-beta 1 in hormone-independent tumors may be related to the acquisition of autonomous growth.
我们研究了生长因子（GF）、其受体（GF-R）和癌基因在调节醋酸甲羟孕酮（MPA）诱导的BALB/c小鼠乳腺肿瘤模型中肿瘤生长方面的作用。我们证明了胰岛素样生长因子家族的两种配体（IGF-I、IGF-II）以及两种类型的受体（IGF-RI、IGF-RII）的存在。MPA上调了激素依赖性细胞系（MPA-D）中IGF-II的mRNA和蛋白质水平。向激素非依赖性表型的进展伴随着IGF-II的高组成性表达以及IGF-IIR数量的显著减少。用于评估IGF在MPA诱导的上皮MPA-D细胞生长中作用的反义策略表明，IGF通过自分泌/内分泌途径介导孕激素诱导的乳腺肿瘤生长。我们还研究了神经调节蛋白（HRG）的作用，HRG是最近确定的c-erbB3和c-erbB4癌基因的配体。HRG mRNA表达仅限于导管起源的肿瘤。MPA在体内诱导HRG表达上调。最后，我们还发现MPA可能通过抑制转化生长因子β1（TGF-β1）的表达对MPA-D细胞系发挥增殖作用，并且激素非依赖性肿瘤中TGF-β1的缺乏表达可能与自主生长的获得有关。
