PI3K/AKT/mTOR pathway regulates the ligand-independent activation of steroid receptors, hormone independence and tumor differentiation in breast cancer

RIGGIO MARINA; POLO MARIA LAURA; BLAUSTEIN MATIAS; COLMAN-LERNER ALEJANDRO; LÜTHY ISABEL; LANARI CLAUDIA; NOVARO VIRGINIA

San Francisco, CA

Encuentro; 2012 UCSF Breast Oncology Program Scientific Retreat; 2012

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 PI3K/AKT 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 pathway with LY294002 or with rapamycin 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, we evaluated the effect of myrAKT1 on two human breast cancer cell lines, IBH-6 and IBH-7. These cell lines developed from two different primary invasive ductal carcinomas, express steroid hormone receptors and grow in immuno-compromised mice giving rise to invasive tumors. In the estrogen-independent IBH-6 cell line, myrAKT1 increased tumor growth without affecting tumor architecture. In the estrogen-dependent IBH-7 cell line, myrAKT1 induced estrogen-independent growth in 70% of the animals accompanied by changes in cell morphology and increase in the expression of the adhesion markers focal adhesion kinase (FAK) and E-cadherin. Finally, we found that, regarding of the cell type, cells expressing myrAKT1 exhibited increased phosphorylation of the progesterone receptor (PR) at Ser190 and Ser294, and of the estrogen receptor (ERa) at Ser118 and Ser167, independently of exogenous MPA or estrogen supply. Thus, our results indicate that depending on the cell context, or other activated signaling pathways, the effect of activation of the PI3K/AKT/mTOR pathway may differ between models, but finally they all collaborate promoting HI tumor growth by the activation of steroid receptors.