Laboratorio de Carcinogénesis Hormonal, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (IBYME-CONICET), Vuelta de Obligado 2490, C1428ADN Buenos Aires, Argentina.
Carcinogenesis. 2012 Mar;33(3):509-18. doi: 10.1093/carcin/bgr303. Epub 2011 Dec 17.
Using a model of medroxyprogesterone acetate (MPA)-induced mouse mammary tumors that transit through different stages of hormone dependence, we previously reported that the activation of the phosphatidylinositol 3-kinase (PI3K)/AKT (protein kinase B) pathway is critical for the growth of hormone-independent (HI) mammary carcinomas but not for the growth of hormone-dependent (HD) mammary carcinomas. The objective of this work was to explore whether the activation of the PI3K/AKT pathway is responsible for the changes in tumor phenotype and for the transition to autonomous growth. We found that the inhibition of the PI3K/AKT/mTOR (mammalian target of rapamycin) pathway suppresses HI tumor growth. In addition, we were able to induce mammary tumors in mice in the absence of MPA by inoculating HD tumor cells expressing a constitutively active form of AKT1, myristoylated AKT1 (myrAKT1). These tumors were highly differentiated and displayed a ductal phenotype with laminin-1 and cytokeratin 8 expression patterns typical of HI tumors. Furthermore, myrAKT1 increased the tumor growth of IBH-6 and IBH-7 human breast cancer cell lines. In the estrogen-dependent IBH-7 cell line, myrAKT1 induced estrogen-independent growth accompanied by the expression of the adhesion markers focal adhesion kinase and E-cadherin. Finally, we found that cells expressing myrAKT1 exhibited increased phosphorylation of the progesterone receptor at Ser190 and Ser294 and of the estrogen receptor α at Ser118 and Ser167, independently of exogenous MPA or estrogen supply. Our results indicate that the activation of the PI3K/AKT/mTOR pathway promotes tissue architecture remodeling and the activation of steroid receptors.
利用醋酸甲羟孕酮（MPA）诱导的小鼠乳腺肿瘤模型，该模型经历不同阶段的激素依赖性，我们之前报道过，磷脂酰肌醇 3-激酶（PI3K）/蛋白激酶 B（AKT）途径的激活对于激素非依赖性（HI）乳腺癌的生长至关重要，但对于激素依赖性（HD）乳腺癌的生长则不重要。本研究的目的是探索 PI3K/AKT 途径的激活是否负责肿瘤表型的变化以及向自主生长的转变。我们发现抑制 PI3K/AKT/mTOR（雷帕霉素靶蛋白）途径可抑制 HI 肿瘤的生长。此外，我们能够通过接种表达组成型激活形式 AKT1（myrAKT1）的 HD 肿瘤细胞，在没有 MPA 的情况下诱导小鼠发生乳腺肿瘤。这些肿瘤高度分化，具有导管表型，表达层粘连蛋白 1 和细胞角蛋白 8，其表达模式与 HI 肿瘤典型。此外，myrAKT1 增加了 IBH-6 和 IBH-7 人乳腺癌细胞系的肿瘤生长。在雌激素依赖性的 IBH-7 细胞系中，myrAKT1 诱导了雌激素非依赖性的生长，同时表达了粘着斑激酶和 E-钙粘蛋白等粘着标记物。最后，我们发现表达 myrAKT1 的细胞表现出孕激素受体 Ser190 和 Ser294 以及雌激素受体α Ser118 和 Ser167 的磷酸化增加，这与外源性 MPA 或雌激素的供应无关。我们的结果表明，PI3K/AKT/mTOR 途径的激活促进了组织结构重塑和类固醇受体的激活。
