Study of PI3K/AKT/mTOR pathway in breast cancer progression

Deregulation in the PI3K/AKT/mTOR pathway is associated with breast cancer development. Using experimental models of breast carcinogenesis induced in mice, xenografts of tumor cell lines, and tumors from patients we found a differential role of AKT1 and AKT2 isoforms in breast cancer 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 and lung metastasis. We analyzed 98 luminal breast carcinomas and found that nuclear AKT1 associates with low grade tumors, while cytosolic AKT2 associates with high grade tumors. Furthermore, presence of cytosolic AKT2 was positively correlated with a shorter time to progression of the disease (earlier relapse). In addition, based on our results 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 isoforms, which maintains AKT2 inhibited while AKT1 prevails in the early stages. In the more advanced stages, this inhibition is lost and AKT2 prevails. Specific miRNAs are good candidates involved in this regulation and are now been tested in our lab in different experimental and clinical conditions. We propose the use of AKT1 and AKT2 isoforms determined by immunohistochemistry as prognostic markers that could help to better stratify breast tumors and direct more specific therapies.Fil: Novaro, Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina54 Annual Meeting Argentine Society for Biochemistry and Molcecular Biology: LIV Reunión Anual Sociedad Argentina de Investigación en Bioquímica y Biología MolecularParanaArgentinaSociedad Argentina de BioquímicaConsejo Nacional de Investigaciones Científicas y TécnicasFondo para la Investigación Científica y Tecnológic

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

The purpose of this study was to elucidate the mechanisms associated with the specific effects of AKT1 and AKT2 isoforms in breast cancer progression. We modulated the abundance of specific AKT isoforms in IBH-6 and T47D human breast cancer cell lines and showed that AKT1 promoted cell proliferation, through S6 and cyclin D1 upregulation, but it inhibited cell migration and invasion through β1-integrin and focal adhesion kinase (FAK) downregulation. In contrast, AKT2 promoted cell migration and invasion through F-actin and vimentin induction. Thus, while overexpression of AKT1 promoted local tumor growth, downregulation of AKT1 or overexpression of AKT2 promoted peritumoral invasion and lung metastasis. Furthermore, we evaluated The Cancer Genome Atlas (TCGA) dataset for invasive breast carcinomas and found that increased AKT2 but not AKT1 mRNA levels correlated with a worse clinical outcome. We conclude that AKT isoforms play specific roles in different steps of breast cancer progression, with AKT1 involved in the local tumor growth and AKT2 involved in the distant tumor dissemination, having AKT2 a poorer prognostic value and consequently being a worthwhile target for therapy.Fil: Riggio, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Perrone, Maria Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Polo, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Rodriguez, Maria Jimena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: May, Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Abba, Martín Carlos. Universidad Nacional de La Plata; ArgentinaFil: Lanari, Claudia Lee Malvina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Novaro, Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin

The BA-BCS 2021: an initial “trial” for integrating basic science and medical progress on breast cancer in a Latin-American country

The first Buenos Aires Breast Cancer Symposium (BA-BCS) was held in a virtual format, between the 17th and the 21st of May 2021. The main goal of the meeting was to facilitate the interaction among physicians and basic researchers from South America and with peers from the rest of the world. To embrace their different interests and concerns, the congress included not only talks on basic, translational and clinical research, but also round tables to discuss diagnostic methods, research financing and biobank management, as well as virtual poster sessions in which the youngest fellows presented their recent findings. This report provides a brief overview of the talks delivered during the meeting, which addressed a wide variety of vital issues for breast cancer research mostly focused on the accurate diagnosis, prevention and treatment of this illness. The presentations included a wide spectrum of themes including hormone receptors and the relevance of their mutations, immunotherapy, cancer stem cells, mouse models, environmental hazards, genetics and epigenetics, local and systemic therapies, liquid biopsies, the metastatic cascade, therapy resistance and dormancy, among others.Fil: Kordon, Edith Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Lanari, Claudia Lee Malvina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Mando, Pablo. Centro de Educación Médica e Investigaciones Clínicas "Norberto Quirno"; ArgentinaFil: Novaro, Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Rossi, Mario. Universidad Austral; ArgentinaFil: Simian, Marina. Universidad Nacional de San Martín; Argentin

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

The purpose of this study was to elucidate the mechanisms associated with the specific effects of AKT1 and AKT2 isoforms in breast cancer progression. We modulated the abundance of specific AKT isoforms in IBH-6 and T47D human breast cancer cell lines and showed that AKT1 promoted cell proliferation, through S6 and cyclin D1 upregulation, but it inhibited cell migration and invasion through β1-integrin and focal adhesion kinase (FAK) downregulation. In contrast, AKT2 promoted cell migration and invasion through F-actin and vimentin induction. Thus, while overexpression of AKT1 promoted local tumor growth, downregulation of AKT1 or overexpression of AKT2 promoted peritumoral invasion and lung metastasis. Furthermore, we evaluated The Cancer Genome Atlas (TCGA) dataset for invasive breast carcinomas and found that increased AKT2 but not AKT1 mRNA levels correlated with a worse clinical outcome. We conclude that AKT isoforms play specific roles in different steps of breast cancer progression, with AKT1 involved in the local tumor growth and AKT2 involved in the distant tumor dissemination, having AKT2 a poorer prognostic value and consequently being a worthwhile target for therapy.Facultad de Ciencias Naturales y MuseoCentro de Investigaciones Inmunológicas Básicas y Aplicada

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

The purpose of this study was to elucidate the mechanisms associated with the specific effects of AKT1 and AKT2 isoforms in breast cancer progression. We modulated the abundance of specific AKT isoforms in IBH-6 and T47D human breast cancer cell lines and showed that AKT1 promoted cell proliferation, through S6 and cyclin D1 upregulation, but it inhibited cell migration and invasion through β1-integrin and focal adhesion kinase (FAK) downregulation. In contrast, AKT2 promoted cell migration and invasion through F-actin and vimentin induction. Thus, while overexpression of AKT1 promoted local tumor growth, downregulation of AKT1 or overexpression of AKT2 promoted peritumoral invasion and lung metastasis. Furthermore, we evaluated The Cancer Genome Atlas (TCGA) dataset for invasive breast carcinomas and found that increased AKT2 but not AKT1 mRNA levels correlated with a worse clinical outcome. We conclude that AKT isoforms play specific roles in different steps of breast cancer progression, with AKT1 involved in the local tumor growth and AKT2 involved in the distant tumor dissemination, having AKT2 a poorer prognostic value and consequently being a worthwhile target for therapy.Facultad de Ciencias Naturales y MuseoCentro de Investigaciones Inmunológicas Básicas y Aplicada

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

The purpose of this study was to elucidate the mechanisms associated with the specific effects of AKT1 and AKT2 isoforms in breast cancer progression. We modulated the abundance of specific AKT isoforms in IBH-6 and T47D human breast cancer cell lines and showed that AKT1 promoted cell proliferation, through S6 and cyclin D1 upregulation, but it inhibited cell migration and invasion through β1-integrin and focal adhesion kinase (FAK) downregulation. In contrast, AKT2 promoted cell migration and invasion through F-actin and vimentin induction. Thus, while overexpression of AKT1 promoted local tumor growth, downregulation of AKT1 or overexpression of AKT2 promoted peritumoral invasion and lung metastasis. Furthermore, we evaluated The Cancer Genome Atlas (TCGA) dataset for invasive breast carcinomas and found that increased AKT2 but not AKT1 mRNA levels correlated with a worse clinical outcome. We conclude that AKT isoforms play specific roles in different steps of breast cancer progression, with AKT1 involved in the local tumor growth and AKT2 involved in the distant tumor dissemination, having AKT2 a poorer prognostic value and consequently being a worthwhile target for therapy.Facultad de Ciencias Naturales y MuseoCentro de Investigaciones Inmunológicas Básicas y Aplicada

Crescimento do câncer de mama receptor de hormônio dependente: contribuições de um modelo experimental

Si bien los estrógenos han demostrado tener un rol protagónico en el cáncer de mama, hoy se sabe que la progesterona, así como sus derivados sintéticos, ejercen roles proliferativos tanto en la glándula mamaria normal como neoplásica. Utilizando un modelo experimental de cáncer mamario murino, iniciado en la Academia Nacional de Medicina y trasladado al IBYME en el año 1995, demostramos la importancia de los fibroblastos asociados a tumor en la provisión de factores de crecimiento que activan en forma ligando-independiente a los receptores de progesterona (RPs) en las células tumorales. En este artículo mencionamos la importancia por un lado de la proporción de isoformas del RP en la determinación de la respuesta al tratamiento hormonal, y por otro, los mecanismos por los cuales el factor de crecimiento fibroblástico 2 (FGF2) estromal participaría en el crecimiento tumoral imitando la acción de la hormonaIt is well known that estrogens are key players regulating breast cancer growth. In addition, there is compelling evidence pointing out that progestins induce proliferative effects in normal and in neoplastic mammary glands. Using a murine breast cancer model, first developed in the National Academy of Medicine in Buenos Aires, and then moved to the IBYME in 1995, we demonstrated that carcinoma associated fibroblasts provide growth factors such as fibroblast growth factor 2 (FGF2), which are involved in the ligand independent activation of progesterone receptors (PR) of tumor cells. This article briefly describes, on one hand, the relevance of the evaluation of the PR isoform ratio to predict hormone responsiveness, and on the other hand, the mechanisms by which stromal FGF2 mimics the effects of progesterone to stimulate tumor growth.Embora os estrógenos tenham demonstrado ter um papel protagônico no câncer de mama, hoje se sabe que a progesterona, bem como seus derivados sintéticos, exerce papéis proliferativos tanto na glândula mamária normal quanto neoplá- sica. Utilizando um modelo experimental de câncer mamário murino, iniciado na Academia Nacional de Medicina e trasladado ao IBYME no ano 1995, demonstramos a importância dos fibroblastos associados a tumor na provisão de fatores de crescimento que ativam em forma ligando-independente os receptores de progesterona (RPs) nas células tumorais. Neste artigo mencionamos a importância, de um lado, da proporção de isoformas do RP na determinação da resposta ao tratamento hormonal, e do outro, dos mecanismos pelos quais o fator de crescimento fibroblástico 2 (FGF2) estromal participaria no crescimento tumoral imitando a ação do hormônio.Fil: Lanari, Claudia Lee Malvina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Novaro, Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Lamb, Caroline Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Fabris, Victoria Teresa. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Rojas, Paola Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Giulianelli, Sebastian Jesus. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Gorostiaga, Maria Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Wargon, Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Guillardoy, Tomás. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Polo, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Riggio, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Sequeira, Gonzalo Ricardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Sahores, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Pampena, María Betina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentin

Beneficial Effects of Mifepristone Treatment in Patients with Breast Cancer Selected by the Progesterone Receptor Isoform Ratio: Results from the MIPRA Trial

Purpose: Preclinical data suggest that antiprogestins inhibit the growth of luminal breast carcinomas that express higher levels of progesterone receptor isoform A (PRA) than isoform B (PRB). Thus, we designed a pre-surgical window of opportunity trial to determine the therapeutic effects of mifepristone in patients with breast cancer based on their high PRA/PRB isoform ratio (MIPRA; NCT02651844).Patients and methods: Twenty patients with luminal breast carcinomas with PRA/PRB>1.5 (determined by western blots), and PR ≥50%, naive from previous treatment, were included for mifepristone treatment (200 mg/day p.o.; 14 days). Core needle biopsies (CNB) and surgical samples were formalin-fixed for immunohistochemical studies, while others were snap-frozen to perform RNA-Seq, proteomics, and/or western blot studies. Plasma mifepristone levels were determined using mass spectrometry. The primary endpoint was the comparison of Ki67 expression pre- and post-treatment.Results: A 49.62% decrease in Ki67 staining was observed in all surgical specimens compared to baseline (p=0.0003). Using the prespecified response parameter (30% relative reduction), we identified 14/20 responders. Mifepristone induced an increase in tumor-infiltrating lymphocytes, a decrease in hormone receptor and pSer118ER expression, and an increase in calregulin, p21, p15, and activated caspase3 expression. RNA-Seq and proteomics studies identified downregulated pathways related to cell proliferation and upregulated pathways related to immune bioprocesses and extracellular matrix remodeling.Conclusions: Our results support the use of mifepristone in patients with luminal breast cancer with high PRA/PRB ratios. The combined effects of mifepristone and estrogen receptor modulators warrant clinical evaluation to improve endocrine treatment responsiveness in these patients.Fil: Elia, Andres Maximiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Saldain, Leo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Vanzulli, Silvia. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Helguero, Luisa Alejandra. Universidade de Aveiro; PortugalFil: Lamb, Caroline Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Fabris, Victoria Teresa. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Pataccini, Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Martínez Vazquez, Paula. Gobierno de la Provincia de Buenos Aires. Hospital Zonal General de Agudos Magdalena Villegas de Martinez.; ArgentinaFil: Burruchaga, Javier. Gobierno de la Provincia de Buenos Aires. Hospital Zonal General de Agudos Magdalena Villegas de Martinez.; ArgentinaFil: Caillet Bois, Ines. Gobierno de la Provincia de Buenos Aires. Hospital Zonal General de Agudos Magdalena Villegas de Martinez.; ArgentinaFil: Spengler, EunicE. Gobierno de la Provincia de Buenos Aires. Hospital Zonal General de Agudos Magdalena Villegas de Martinez.; ArgentinaFil: Acosta Haab, Gabriela. Gobierno de la Provincia de Buenos Aires. Hospital Zonal General de Agudos Magdalena Villegas de Martinez.; ArgentinaFil: Liguori, Marcos Daniel. Gobierno de la Provincia de Buenos Aires. Hospital Zonal General de Agudos Magdalena Villegas de Martinez.; ArgentinaFil: Castets, Alejandra. Gobierno de la Provincia de Buenos Aires. Hospital Zonal General de Agudos Magdalena Villegas de Martinez.; ArgentinaFil: Lovisi, Silvia. Gobierno de la Provincia de Buenos Aires. Hospital Zonal General de Agudos Magdalena Villegas de Martinez.; ArgentinaFil: Abascal, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Novaro, Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Sánchez, Jana. Centro Nacional de Investigaciones Oncológicas; EspañaFil: Muñoz, Javier. Centro Nacional de Investigaciones Oncológicas; EspañaFil: Belizán, José M.. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Abba, Martín Carlos. Universidad Nacional de La Plata. Facultad de Ciencias Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Gass, Hugo Daniel. Gobierno de la Provincia de Buenos Aires. Hospital Zonal General de Agudos Magdalena Villegas de Martinez.; ArgentinaFil: Rojas, Paola Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Lanari, Claudia Lee Malvina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin