Protein Kinases and Cancer

Our aim is to understand the role of protein kinases, in particular the role of PI3K/Akt/mTOR, in breast cancer progression. Using diverse pre-clinical models of breast cancer we have focused on two crucial events in mammary gland carcinogenesis. First, we have demonstrated PI3K/Akt/mTOR involvement in hormone-independent tumor growth and endocrine resistance. Second, we asked how and in which tumor types PI3K/Akt/mTOR inhibitors contribute to the efficacy of the endocrine therapy, or even if the inhibitors could replace it when the endocrine therapy has become ineffective in inducing tumor regression. For this, we have recently initiated the evaluation of PI3K/Akt/mTOR pathway activation in human samples of breast cancer at different stages. 

Protein Kinases and Cancer

  • Lab Director

    Virginia Novaro Currículum Vitae
  • Postdoctoral Fellow

    Marina Riggio
  • PhD. Fellow

    María Cecilia Perrone
  • PhD Fellow

    María Jimena Rodriguez

Role of PI3K/Akt/mTOR pathway in breast cancer progression and regression

Breast cancer is the second most common cancer worldwide, second only to lung cancer. It has been estimated for 2014 that 1.6 millon of new cases around the world occurred. In Argentina, second after Uruguay in Latinoamerica, breast cancer has the highest mortality rate (20,1 deaths in 100.000 women; Instituto Nacional de Cáncer year 2012 Almost 70% of breast tumors express endocrine receptors to estrogen (ER) and progesterone (PR). Targeted therapy to interfere with estradiol synthesis or ER signaling is the most frequent therapy in use for this type of tumors. Even though endocrine therapy is effective, a high percentage of ER/PR positive tumors are non-responsive from the beginning of the therapy, or they develop resistance leading to tumor recurrence. Understanding the mechanisms involved in endocrine resistance is one of the biggest challenges in the fight against breast cancer. Furthermore, in the last few years, advantages were pursued in the search of combination therapies between endocrine agents and protein kinase inhibitors to avoid endocrine resistance.

In the Protein Kinases and Cancer Laboratory (IBYME-CONICET), we want to identify molecular mechanisms involved in endocrine resistance in breast cancer. This would allow us to anticipate endocrine resistance and design alternative specific therapies to delay or prevent resistance. With this goal in mind, we have focused in paracrine factors from the tumor microenvironment, especially originating in the stroma during tumor growth and tumor regression after therapy; and in intracellular pathways driven by protein kinases such as PI3K/Akt/mTOR. In particular, we have focused in the understanding of how this pathway is involved in the activation of ER and PR and on how this activation in turn affects endocrine sensitivity and response of tumor cells. Furthermore, we have studied differential functions of Akt1 and Akt2 isoforms in the tumor phenotype, and we have found that both isoforms play opposite roles on the regulation of tumor cell migration and invasion.

We use breast cancer cell xenografts and a murine experimental model developed and characterized by Dr. Claudia Lanari at IBYME. This model is relevant because it reproduces the main characteristics of the most frequent breast cancer in patients: ductal histology, ER/PR positive that transitions to hormone-independence. In these pre-clinical models we search for early predictive markers of antitumor therapy efficacy. In addition, such tumor models have allowed us to study another aspect of breast cancer that has not really been pursued in the literature: the process of tumor regression caused by the therapy. For that, we have used a combination of endocrine and PI3K/mTOR inhibitors, searching for molecular and tissue mechanisms affected by each agent. We have recently incorporated human biopsies of breast cancer at the time of surgery, in order to extrapolate pre-clinical parameters into the clinic. In such samples we look for biomarkers to select patients who will benefit from the incorporation of PI3K/Akt/mTOR inhibitors to an endocrine therapy standard protocol. Our results could be relevant to other types of tumors, especially those with endocrine regulation such as prostate cancer, since similar mechanisms involved in protein kinases regulation could be involved in diverse systems.

We have been collaborating for many years with Dr. Claudia Lanari at IBYME with whom we are continuing characterizing the role of progesterone and fibroblast growth factor (FGF) in mammary pathogenesis; with Dr. Alejandro Colman Lerner at FCEN-University of Buenos Aires with whom we design viral vectors for specific manipulation of protein kinases; and with Dr. Derek Radisky from Mayo Clinic at Jacksonville Florida USA, with whom we have incorporated DNA and tissue arrays to analyze the genetic profile of experimental mammary tumors before and after endocrine therapy. In 2013 we have initiated two observational clinical studies using samples from hormone receptor positive breast cancer patients. Such studies are in collaboration with two local hospitals, Hospital Provincial de Neuquén with Dr. Julián Iturbe and Dr. Ariel Zwenger, and Centro Oncológico Riojano Integral with Dr. Diego Lucas Kaen; and with Mayo Clinic at Jacksonville USA with Dr. Derek Radisky.

PI3K/Akt/mTOR in breast cancer progression