Activation of PI3K/Akt/mTOR signaling in the tumor stroma drives endocrine therapy-dependent breast tumor regression

Abstract

Improved efficacy of neoadjuvant endocrine-targeting therapies in luminal breast carcinomas could be achieved with optimal use of pathway targeting agents. In a mouse model of ductal breast carcinoma we identify a tumor regressive stromal reaction that is induced by neoadjuvant endocrine therapy. This reparative reaction is characterized by tumor neovascularization accompanied by infiltration of immune cells and carcinoma-associated fibroblasts that stain for phosphorylated ribosomal protein S6 (pS6), downstream the PI3K/Akt/mTOR pathway. While tumor variants with higher PI3K/Akt/mTOR activity respond well to a combination of endocrine and PI3K/Akt/mTOR inhibitors, tumor variants with lower PI3K/Akt/mTOR activity respond more poorly to the combination therapy than to the endocrine therapy alone, associated with inhibition of stromal pS6 and the reparative reaction. In human breast cancer xenografts we confirm that such differential sensitivity to therapy is primarily determined by the level of PI3K/Akt/mTOR in tumor cells. We further show that the clinical response of breast cancer patients undergoing neoadjuvant endocrine therapy is associated with the reparative stromal reaction. We conclude that tumor level and localization of pS6 are associated with therapeutic response in breast cancer and represent biomarkers to distinguish which tumors will benefit from the incorporation of PI3K/Akt/mTOR inhibitors with neoadjuvant endocrine therapy.

MARCKS contributes to stromal cancer-associated fibroblast activation and facilitates ovarian cancer metastasis

“…Mechanistically, MARCKS carries out the actin cytoskeleton arrangement function with its polybasic effector domain that cross-links actin filaments into bundles and sequesters bisphosphate (PIP2) [40], which is a component of phosphatidylinositol 3′-kinase (PI3K)/AKT pathways. Accordingly, it was recently reported that activation of the PI3K/Akt signaling cascade in the tumor stroma drives breast tumor regression [52], emphasizing the pivotal role of AKT in CAFs as in tumor cells. In addition, a key EMT transcriptional factor, Twist1, was shown to be responsible for MARCKS action on CAF characteristics, similar to that Twist1 induced the transformation of normal fibroblasts in gastric cancer [43].…”

AKT1 and AKT2 isoforms play distinct roles during breast cancer progression through the regulation of specific downstream proteins

“…T47D human cell line requires a previous injection of 0,25 mg of 17β-estradiol to grow in NSG mice28.…”

Non-immunosuppressive triazole-based small molecule induces anticancer activity against human hormone-refractory prostate cancers: the role in inhibition of PI3K/AKT/mTOR and c-Myc signaling pathways

“…A variety of reports have suggested the importance of the PI3K/Akt/mTOR pathway through p70S6K- and 4EBP1-mediated translational regulation on cell proliferation and survival [3–5, 29]. The data demonstrated the activities on the Akt/mTOR signaling including the phosphorylation of Akt at both Thr308 and Ser473 residues in the activation loop and hydrophobic motif of the kinase, respectively, and phosphorylation of mTOR at Ser2448 that was dependent on the kinase activity (Figure 3B) [30, 31].…”

“…mTOR regulates various components involved in protein synthesis, in particular at G1 phase, including initiation and elongation factors, and biogenesis of ribosomes themselves [29–33]. The data revealed that SPS-7 caused a profound inhibition of mTOR and related translational pathways, resulting in the down-regulation of cyclin D1 protein expression and G1 arrest of the cell cycle.…”