PI3K/AKT pathway regulates phosphorylation of steroid receptors, hormone independence and tumor differentiation in breast cancer

Abstract

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.

MicroRNA-374a activates Wnt/β-catenin signaling to promote breast cancer metastasis

“…Cellular signaling pathways, including the Wnt/β-catenin, ERK/MAPK, and PI3K/ Akt pathways, have been found to be aberrantly activated and play vital roles in the development and progression of breast cancer (35)(36)(37). Among these pathways, the prometastatic functions of Wnt/β-catenin signaling in breast cancer have been well documented (35,38).…”

Galangin inhibits growth of human head and neck squamous carcinoma cells in vitro and in vivo

“…In recent years, it has been reported that the AKT/mTOR signaling pathway plays a crucial role in cancer development. Many studies have indicated that this pathway is aberrantly activated in multiple types of cancer, including breast cancer, gastric cancer, acute lymphoblastic leukemia, hepatocellular carcinoma and HNC [24][25][26][27][28]. As a result, the frequent dysregulation of this signaling pathway makes it an important target in cancer therapy [29,30].…”

Comprehensive analysis of PTEN status in breast carcinomas

“…Previous reports have described similar results 44,45 and furthermore an improved survival was observed for patients with PIK3CA mutations in the PR1 tumor subgroup. 44 Although an association between the PI3K pathway and PR regulation has been proposed, 46 is not clear at present what significance this finding has. PR status has no impact on the response to tamoxifen treatment in ER1 tumors 47 but recent evidence suggests that different mechanisms of PI3K pathway activation confer different sensitivities to targeted therapies 48 ; thus, their characterization could guide treatment decisions.…”