Authors: Lamb, Caroline Ana; Fabris, Victoria Teresa; Jacobsen, Britta M.; Molinolo, Alfredo; Lanari, Claudia Lee Malvina
Publication Date: 2018.
Language: English.
Abstract:
There is a consensus that progestins and thus their cognate receptor molecules, the progesterone receptors (PRs), are essential in the development of the adult mammary gland and regulators of proliferation and lactation. However, a role for natural progestins in breast carcinogenesis remains poorly understood. A hint to that possible role came from studies in which the synthetic progestin medroxyprogesterone acetate was associated with an increased breast cancer risk in women under hormone replacement therapy. However, progestins have also been used for breast cancer treatment and to inhibit the growth of several experimental breast cancer models. More recently, PRs have been shown to be regulators of estrogen receptor signaling. With all this information, the question is how can we target PR, and if so, which patients may benefit from such an approach? PRs are not single unique molecules. Two main PR isoforms have been characterized, PRA and PRB, which exert different functions and the relative abundance of one isoform with respect to the other determines the response of PR agonists and antagonists. Immunohistochemistry with standard antibodies against PR do not discriminate between isoforms. In this review, we summarize the current knowledge on the expression of both PR isoforms in mammary glands, in experimental models of breast cancer and in breast cancer patients, to better understand how the PRA/PRB ratio can be exploited therapeutically to design personalized therapeutic strategies.
Author affiliation: 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; Argentina
Author affiliation: 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; Argentina
Author affiliation: Jacobsen, Britta M.. State University of Colorado - Fort Collins; Estados Unidos
Author affiliation: Molinolo, Alfredo. University of California at San Diego; Estados Unidos
Author affiliation: 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; Argentina
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Authors: Sahores, Ana; Figueroa, Virginia; May, Maria; Liguori, Marcos; Rubstein, Adrián; Fuentes, Cynthia Analia; Jacobsen, Britta M.; Elia, Andres Maximiliano; Rojas, Paola Andrea; Sequeira, Gonzalo Ricardo; Álvarez, Michelle M.; González, Pedro; Gass, Hugo; Hewitt, Stephen; Molinolo, Alfredo; Lanari, Claudia Lee Malvina; Lamb, Caroline Ana
Publication Date: 2018.
Language: English.
Abstract:
Endocrine resistance may develop as a consequence of enhanced growth factor signaling. Fibroblast growth factor 2 (FGF2) consists of a low and several high molecular weight forms (HMW-FGF2). We previously demonstrated that antiprogestin-resistant mammary carcinomas display lower levels of progesterone receptor A isoforms (PRA) than B isoforms (PRB). Our aim was to evaluate the role of FGF2 isoforms in breast cancer progression. We evaluated FGF2 expression, cell proliferation, and pathway activation in models with different PRA/PRB ratios. We performed lentiviral infections of different FGF2 isoforms using the human hormone-responsive T47D-YA cells, engineered to only express PRA, and evaluated tumor growth, metastatic dissemination, and endocrine responsiveness. We assessed FGF2 expression and localization in 81 human breast cancer samples. Antiprogestin-resistant experimental mammary carcinomas with low PRA/PRB ratios and T47D-YB cells, which only express PRB, displayed higher levels of HMW-FGF2 than responsive variants. HMW-FGF2 overexpression in T47D-YA cells induced increased tumor growth, lung metastasis, and antiprogestin resistance compared to control tumors. In human breast carcinomas categorized by their PRA/PRB ratio, we found nuclear FGF2 expression in 55.6% of tumor cells. No differences were found between nuclear FGF2 expression and Ki67 proliferation index, tumor stage, or tumor grade. In low-grade tumor samples, moderate to high nuclear FGF2 levels were associated to carcinomas with low PRA/PRB ratio. In conclusion, we show that HMW-FGF2 isoforms are PRB targets which confer endocrine resistance and are localized in the nuclei of breast cancer samples. Hence, targeting intracellular FGF2 may contribute to overcome tumor progression.
Author affiliation: Sahores, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina
Author affiliation: Figueroa, Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Author affiliation: 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; Argentina
Author affiliation: Liguori, Marcos. Hospital de Agudos Magdalena V de Martínez; Argentina
Author affiliation: Rubstein, Adrián. Merck Argentina; Argentina
Author affiliation: Fuentes, Cynthia Analia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Author affiliation: Jacobsen, Britta M.. University Of Colorado At Denver Anschutz Medical Campus;
Author affiliation: 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; Argentina
Author affiliation: 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; Argentina
Author affiliation: Sequeira, Gonzalo Ricardo. 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; Argentina
Author affiliation: Álvarez, Michelle M.. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Author affiliation: González, Pedro. Hospital de Agudos Magdalena V de Martínez; Argentina
Author affiliation: Gass, Hugo. Hospital de Agudos Magdalena V de Martínez; Argentina
Author affiliation: Hewitt, Stephen. National Institute Of Dental And Craniofacial Research;
Author affiliation: Molinolo, Alfredo. Ucsd Medical Center, Moores Cancer Center;
Author affiliation: 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; Argentina
Author affiliation: 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; Argentina
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Authors: Salatino, Mariana; Schillaci, Roxana; Proietti Anastasi, Cecilia Jazmín; Carnevale, Romina Paula; Frahm, Isabel; Molinolo, Alfredo; Iribarren, Adolfo Marcelo; Charreau, Eduardo Hernan; Elizalde, Patricia Virginia
Publication Date: 2004.
Language: English.
Abstract:
The present study addresses the effect of targeting type I insulin-like growth factor receptor (IGF-IR) with antisense strategies in in vivo growth of breast cancer cells. Our research was carried out on C4HD tumors from an experimental model of hormonal carcinogenesis in which the synthetic progestin medroxyprogesterone acetate (MPA) induced mammary adenocarcinomas in Balb/c mice. We employed two different experimental strategies. With the first one we demonstrated that direct intratumor injection of phosphorothioate antisense oligodeoxynucleotides (AS[S]ODNs) to IGF-IR mRNA resulted in a significant inhibition of C4HD tumor growth. In the second experimental strategy, we assessed the effect of intravenous (i.v.) injection of AS [S]ODN on C4HD tumor growth. This systemic treatment also resulted in significant reduction in tumor growth. The antitumor effect of IGF-IR AS[S]ODNs in both experimental protocols was due to a specific antisense mechanism, since growth inhibition was dose-dependent and no abrogation of tumor proliferation was observed in mice treated with phosphorothioate sense ODNs (S[S]ODNs). In addition, IGF-IR expression was inhibited in tumors from mice receiving AS[S]ODNs, as compared to tumors from control groups. We then investigated signal transduction pathways modulated in vivo by AS[S]ODNs treatment. Tumors from AS[S]ODN-treated mice of both intratumoral and intravenous protocols showed a significant decrease in the degree of insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation. Activation of two of the main IGF-IR signaling pathways, phosphatidylinositol 3-kinase (PI-3K)/Akt and p42/p44 mitogen-activated protein kinases (MAPK) was abolished in tumors growing in AS[S]ODN-treated animals. Moreover, ErbB-2 tyrosine phosphorylation was blocked by in vivo administration of AS[S]ODNs. On the other hand, we found no regulation of either progesterone receptor expression or activity by in vivo AS[S]ODNs administration. Our results for the first time demonstrated that breast cancer growth can be inhibited by direct in vivo administration of IGF-IR AS[S]ODNs.
Author affiliation: Salatino, Mariana. 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; Argentina
Author affiliation: Schillaci, Roxana. 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; Argentina
Author affiliation: Proietti Anastasi, Cecilia Jazmín. 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; Argentina
Author affiliation: Carnevale, Romina Paula. 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; Argentina
Author affiliation: Frahm, Isabel. Sanatorio Mater Dei Hermanas de María de Schönstat; Argentina
Author affiliation: Molinolo, Alfredo. 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; Argentina
Author affiliation: Iribarren, Adolfo Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Author affiliation: Charreau, Eduardo Hernan. 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; Argentina
Author affiliation: Elizalde, Patricia 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; Argentina
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Authors: Fabris, Victoria Teresa; Abascal, Maria Florencia; Giulianelli, Sebastian Jesus; May, María; Sequeira, Gonzalo Ricardo; Jacobsen, Britta; Lombès, Marc; Han, Julie; Tran, Luan; Molinolo, Alfredo; Lanari, Claudia Lee Malvina
Publication Date: 2017.
Language: English.
Abstract:
Progesterone receptors (PR) are prognostic and predictive biomarkers in hormone-dependent cancers. Twomain PR isoforms have been described, PRB and PRA, that differ only in that PRB has 164 extra N-terminalamino acids. It has been reported that several antibodies empirically exclusively recognize PRA in formalinfixedparaffin-embedded (FFPE) tissues. To confirm these findings, we used human breast cancer xenograftmodels, T47D-YA and -YB cells expressing PRA or PRB, respectively, MDA-MB-231 cells modified to synthesizePRB, and MDA-MB-231/iPRAB cells which can bi-inducibly express either PRA or PRB. Cells were injectedinto immunocompromised mice to generate tumours exclusively expressing PRA or PRB. PR isoform expressionwas verified using immunoblots. FFPE samples from the same tumours were studied by immunohistochemistryusing H-190, clone 636, clone 16, and Ab-6 anti-PR antibodies, the latter exclusively recognizing PRB. Exceptfor Ab-6, all antibodies displayed a similar staining pattern. Our results indicate that clones 16, 636, and theH-190 antibody recognize both PR isoforms. They point to the need for more stringency in evaluating thetrue specificity of purported PRA-specific antibodies as the PRA/PRB ratio may have prognostic and predictivevalue in breast cancer.
Author affiliation: 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; Argentina
Author affiliation: 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; Argentina
Author affiliation: Giulianelli, Sebastian Jesus. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto de Biología de Organismos Marinos; Argentina
Author affiliation: May, María. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina
Author affiliation: Sequeira, Gonzalo Ricardo. 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; Argentina
Author affiliation: Jacobsen, Britta. University of Colorado Anschutz Medical Campus; Estados Unidos
Author affiliation: Lombès, Marc. Inserm; Francia
Author affiliation: Han, Julie. Moore´s Cancer Center; Estados Unidos
Author affiliation: Tran, Luan. Moore´s Cancer Center; Estados Unidos
Author affiliation: Molinolo, Alfredo. 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; Argentina
Author affiliation: 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; Argentina
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Authors: Rojas, Paola Andrea; May, Maria; Sequeira, Gonzalo Ricardo; Elia, Andres Maximiliano; Alvarez, Michelle; Martínez, Paula; González, Pedro; Hewitt, Stephen; He, Xiaping; Perou, Charles M.; Molinolo, Alfredo; Gibbons, Luz; Abba, Martín Carlos; Gass, Hugo; Lanari, Claudia Lee Malvina
Publication Date: 2017.
Language: English.
Abstract:
Compelling evidence shows that progestins regulate breast cancer growth. Using preclinical models, we demonstrated that antiprogestins are inhibitory when the level of progesterone receptor isoform A (PR-A) is higher than that of isoform B (PR-B) and that they might stimulate growth when PR-B is predominant. The aims of this study were to investigate ex vivo responses to mifepristone (MFP) in breast carcinomas with different PR isoform ratios and to examine their clinical and molecular characteristics.
Author affiliation: 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; Argentina
Author affiliation: 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; Argentina
Author affiliation: Sequeira, Gonzalo Ricardo. 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; Argentina
Author affiliation: 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; Argentina
Author affiliation: Alvarez, Michelle. Provincia de Buenos Aires. Hospital Zonal General de Agudos Magdalena Villegas de Martínez; Argentina
Author affiliation: Martínez, Paula. Provincia de Buenos Aires. Hospital Zonal General de Agudos Magdalena Villegas de Martínez; Argentina
Author affiliation: González, Pedro. Provincia de Buenos Aires. Hospital Zonal General de Agudos Magdalena Villegas de Martínez; Argentina
Author affiliation: Hewitt, Stephen. National Institutes of Health; Estados Unidos
Author affiliation: He, Xiaping. University of North Carolina; Estados Unidos
Author affiliation: Perou, Charles M.. University of North Carolina; Estados Unidos
Author affiliation: Molinolo, Alfredo. University of California at San Diego; Estados Unidos
Author affiliation: Gibbons, Luz. Instituto de Efectividad Clínica y Sanitaria; Argentina
Author affiliation: Abba, Martín Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina
Author affiliation: Gass, Hugo. Provincia de Buenos Aires. Hospital Zonal General de Agudos Magdalena Villegas de Martínez; Argentina
Author affiliation: 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; Argentina
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas
Authors: Wargon, Victoria; Riggio, Marina; Giulianelli, Sebastian Jesus; Sequeira, Gonzalo Ricardo; Rojas, Paola Alejandra; May, Maria; Polo, Maria Laura; Gorostiaga, Maria Alicia; Jacobsen, Britta; Molinolo, Alfredo; Novaro, Virginia; Lanari, Claudia Lee Malvina
Publication Date: 2014.
Language: English.
Abstract:
There is emerging interest in understanding the role of progesterone receptors (PRs) in breast cancer. The aim of this study was to investigate the proliferative effect of progestins and antiprogestins depending on the relative expression of the A (PRA) and B (PRB) isoforms of PR. In mifepristone (MFP)-resistant murine carcinomas antiprogestin responsiveness was restored by re-expressing PRA using demethylating agents and histone deacetylase inhibitors. Consistently, in two human breast cancer xenograft models, one manipulated to overexpress PRA or PRB (IBH-6 cells), and the other expressing only PRA (T47D-YA) or PRB (T47D-YB), MFP selectively inhibited the growth of PRA-overexpressing tumors and stimulated IBH-6-PRB xenograft growth. Furthermore, in cells with high or equimolar PRA/PRB ratios, which are stimulated to proliferate in vitro by progestins, and are inhibited by MFP, MPA increased the interaction between PR and the coactivator AIB1, and MFP favored the interaction between PR and the corepressor SMRT. In a PRB-dominant context in which MFP stimulates and MPA inhibits cell proliferation, the opposite interactions were observed. Chromatin immunoprecipitation assays in T47D cells in the presence of MPA or MFP confirmed the interactions between PR and the coregulators at the CCND1 and MYC promoters. SMRT downregulation by siRNA abolished the inhibitory effect of MFP on MYC expression and cell proliferation. Our results indicate that antiprogestins are therapeutic tools that selectively inhibit PRA-overexpressing tumors by increasing the SMRT/AIB1 balance at the CCND1 and MYC promoters.
Author affiliation: Wargon, Victoria. 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; Argentina
Author affiliation: Riggio, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina
Author affiliation: Giulianelli, Sebastian Jesus. 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; Argentina
Author affiliation: Sequeira, Gonzalo Ricardo. 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; Argentina
Author affiliation: Rojas, Paola Alejandra. 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; Argentina
Author affiliation: 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; Argentina
Author affiliation: 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; Argentina
Author affiliation: Gorostiaga, Maria Alicia. 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; Argentina
Author affiliation: Jacobsen, Britta. University of Colorado Anschutz Medical Campus; Estados Unidos
Author affiliation: Molinolo, Alfredo. Oral and Pharyngeal Cancer Branch; Estados Unidos
Author affiliation: 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; Argentina
Author affiliation: 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; Argentina
Keywords: cáncer de mama; receptores hormonales; isoforma del receptor de progesterona; resistencia endócrina; breast cancer; progesterone receptor isoforms; antipro- gestins; mifepristone; AIB1; SMRT; cyclin D1; MYC; antiprogestin therapy; hormone responsiveness; Patología; Medicina Básica; CIENCIAS MÉDICAS Y DE LA SALUD.
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas