Study of the prognostic and predictive values of AKT and S6 in breast cancer

MARÍA CECILIA PERRONE; DIEGO ENRICO; NOVARO VIRGINIA; MARÍA JIMENA RODRIGUEZ; ZWENGER ARIEL; MARINA RIGGIO; LUCÍA ALCOBER BOQUET

Conferencia; Second AACR International Conference. Translational Cancer Medicine, Cancer Discoveries for Clinical Application; 2018

Deregulation in the PI3K/AKT/mTOR pathway is associated with breast cancer progression; however, the use of selective inhibitors, alone or in combination with other agents, is not completely effective. We postulate that failure is largely due to the fact that some tumors do not have the pathway activated despite having the PIK3CA mutation, and thus, should not be expected to respond to its inhibition.We measured by immunohistochemistry the presence of different components of the PI3K/Akt/mTOR pathway, as possible prognostic and predictive markers for breast cancer. Here we report our results related to AKT isoforms and phosphorylation of ribosomal protein S6 (pS6). We analyzed 31 luminal breast carcinomas in early stages. We found that in stage I tumors nuclear AKT1 was higher than AKT2, while in stage II and III tumors the level of AKT2 was higher. In 39 samples of luminal breast carcinomas in advanced stage, presence of nuclear AKT1 was positively associated with the degree of Ki67 (proliferation index), whereas presence of AKT2 was positively correlated with a shorter time to progression of the disease (earlier relapse). Using experimental models of breast carcinogenesis induced in mice and in xenografts of T47D and MCF-7 cell lines, we confirmed the differential role of AKT1 and AKT2 in tumor progression. That is, AKT1 regulates nuclear proteins related to cell proliferation, such as cyclin D1 and pS6, whereas AKT2 regulates proteins related to cell migration and invasion such as vimentin, integrin b1, F-actin and FAK. Furthermore, activation of AKT1 promoted the hormone-independent and endocrine resistant phenotype, whereas activation of AKT2 lead to a more aggressive phenotype. In addition, based on results obtained in these experimental models and data analysis from public databases of The Cancer Genome Atlas, we postulate that throughout the progression of the disease there would be a switch between AKT1 and AKT2, which maintains AKT2 inhibited while AKT1 prevails in the early stages, but that in the more advanced stages, this inhibition is lost and AKT2 prevails.As for predictive value, we analyzed data from 39 stage III breast tumors. We found that pS6 after neoadjuvant chemotherapy was associated with tumor infiltration of lymphocytes and with reduction of tumor size. Previously, we have demonstrated that pS6 was also associated with tumor shrinkage after neoadjuvant endocrine therapy. We are currently studying in experimental models of neoadjuvant therapy, the role of pS6 in the stromal reaction during the therapeutic response and in tumor recurrence.In summary, we began to understand how the PI3K/AKT/mTOR pathway is modified during the progression of luminal breast tumors, how its activation accompanies the clinical response, and the molecular mechanisms responsible for its regulation throughout the development of the disease. We postulate that levels of AKT isoforms could constitute a relevant prognostic marker, and that of pS6 could constitute a predictive marker.