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Fil: Puricelli, Lydia Ines. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina Fil: Bal de Kier Joffe, Elisa. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología; Argentina Fil: Eynard, Aldo Renato. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina

Breast cancer progression and metastasis have been linked to abnormal signaling by transforming growth factor-beta (TGF-beta) cytokines. In early-stage breast cancers, TGF-beta exhibits tumor suppressor activity by repressing cell proliferation and inducing cell death, whereas in advanced-stage tumors, TGF-beta promotes invasion and metastatic dissemination. The molecular mechanisms underlying pro-oncogenic activities of TGF-beta are not fully understood. The present study validates the role of TGF-beta signaling in cancer progression and explores mediators of pro-oncogenic TGF-beta activities using the LM3 mammary adenocarcinoma cell line, derived from a spontaneous murine mammary adenocarcinoma. Expression of kinase-inactive TGF-beta receptors decreased both basal and TGF-beta-induced invasion. Analysis of signal transduction mediators showed that p38MAPK and MEK contribute to TGF-beta stimulation of cell motility and invasion. TGF-beta disrupted the epithelial actin structures supporting cell-cell adhesions, and increased linear actin filaments. Moreover, MEK and p38MAPK pathways showed opposite effects on actin remodeling in response to TGF-beta. Blockade of Raf-MEK signaling enhanced TGF-beta induction of actin stress-fibers whereas p38MAPK inhibitors blocked this effect. A novel observation was made that TGF-beta rapidly activates the actin nucleation Arp2/3 complex. In addition, TGF-beta stimulated matrix metalloproteinase MMP-9 secretion via a MAPK-independent pathway. Experiments using syngeneic mice showed that kinase-inactive TGF-beta receptors inhibit the first stages of LM3 tumor growth in vivo. Our studies demonstrate that autocrine TGF-beta signaling contributes to the invasive behavior of mammary carcinoma cells. Moreover, we show that both MAPK-dependent and -independent pathways are necessary for TGF-beta-induced effects. Therefore, MEK-ERK and p38 MAPK pathways are potential venues for therapeutic intervention in pro-oncogenic TGF-beta signaling. Fil: Daroqui, Maria Cecilia. Montefiore Medical Center; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Vazquez, Paula. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncologia "Angel H. Roffo"; Argentina Fil: Bal, Elisa Dora. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncologia "Angel H. Roffo"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Bakin, Andrei V.. Roswell Park Cancer Institute; Estados Unidos Fil: Puricelli, Lydia I.. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncologia "Angel H. Roffo"; Argentina

Glypicans represent a family of cell surface proteoglycans. Loss-of-function mutations in the human glypican-3 (GPC3) gene results in the Simpson-Golabi- Behmel syndrome, characterized by severe malformations and pre- and postnatal overgrowth. Because the expression of GPC3 during human embryonic and fetal periods remains largely unknown, we investigated by immunohistochemistry its pattern of expression during four periods of human development covering the embryonic period (P1) from 5 to 8 weeks of development, and the fetal periods (P2, P3 and P4) from 9 to 28 weeks of development. Hepatocytes were homogeneously positive for GPC3 during the four periods while pancreatic acini and ducts showed a rather high staining only during P1. GPC3 was also detected in several kidney structures and in the genital system where the sex cords were weakly positive in P1 and P2. In later developmental stages the male’s genital system expressed GPC3 while the female’s did not. While the mesenchyme in the limbs showed positive staining in P1, GPC3 was not detected during the following stages. The mesenchymal tissue localized between the most caudal vertebrae was also positive in P1. A strong GPC3 signal was observed in neurons of the spinal cord and dorsal root ganglia in P2 and P3, while the brain was negative. In sum our studies revealed that GPC3 expression is highly tissue- and stage-specific during human development. The expression pattern of GPC3 is consistent with the abnormalities seen in the Simpson- Golabi-Behmel syndrome.

Silencing of fibronectin (FN) expression seems to be one of the key mechanisms underlying metastatic behaviour. An inverse correlation exists between FN expression levels and the metastatic potential of two related murine mammary adenocarcinomas, M3 and MM3. Primary cultures of M3 tumour, which is moderately metastatic to lung (40% incidence), show a conspicuous FN extracellular matrix (ECM) and high levels of FN mRNA, while primary cultures of the highly metastatic MM3 tumour (95% lung incidence) are negative for FN in immunofluorescence and show at least 40‐fold lower levels of FN mRNA, only detectable by RT‐PCR, with a different pattern of alternatively spliced EDI isoforms compared to M3 cells. We show that the FN promoter sequence is not altered in MM3 cells. Transfection experiments with CAT constructs indicate that silencing occurs at the transcriptional level, involving the 220‐bp proximal promoter region. Fil: Werbajh, Santiago Enrique. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular. Laboratorio de Fisiología y Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Urtreger, Alejandro Jorge. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Puricelli, Lydia Ines. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Sacerdote de Lustig, Eugenia. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Bal, Elisa Dora. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina Fil: Kornblihtt, Alberto Rodolfo. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular. Laboratorio de Fisiología y Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Unidad documental simple