INVESTIGADORES
GIULIANELLI Sebastian Jesus
congresos y reuniones científicas
Título:
STROMAL SIGNALS AND THE PI3K/AKT PATHWAY REGULATE HORMONE SENSITIVITY IN A MOUSE MAMMARY TUMOR MODEL
Autor/es:
MARINA RIGGIO; JUAN PABLO CERLIANI; ALEJANDRO-COLMAN LERNER; SEBASTIAN GIULIANELLI; VICTORIA WARGON; MATIAS BLAUSTEIN; MAR√ćA LAURA POLO; CLAUDIA LANARI; VIRGINIA NOVARO
Lugar:
Salve Regina University. Newport, RI. USA
Reunión:
Conferencia; Gordon Research Conferences - Mammary Gland Biology; 2009
Resumen:
Protein kinases integrate cellular responses to diverse extracellular signals to ultimately control breast tumor growth even in the absence of steroid hormones. Using a mouse mammary tumor model induced by medroxyprogesterone acetate (MPA) we have previously reported that the activation of PI3K/Akt pathway is involved in the growth of a hormone-independent (C4-HI) tumor variant but not in a hormone-dependent (C4-HD) tumor; and it induces progesterone (PR) and estrogen receptor (ER) expression in epithelial C4-HI tumor cells. Our hypothesis is that in the C4-HI tumor the PI3K/AKT pathway is prevalent in regulating steroid receptors and cellular proliferation, whereas in the C4-HD tumor the predominant pathway is governed by MPA. In this work, first we have analyzed DNA microarrays in tumor samples and found that PTEN is higher in C4-HD tumors than in C4-HI tumors, and the reverse is true for PDK1 levels. Second, PR, PI3K/AKT, and proliferation are all induced in tumor epithelial cells in the presence of conditioned medium (CM) derived from C4-HI tumor associated fibroblasts (CAFs), but not from C4-HD tumor CAFs. Third, the activity of C4-HI-CAF derived CM is abolished by anti-FGF-2 blocking antibodies, suggesting that FGF-2 is a key factor in this stromal/epithelian interaction. Finally, we were able to generate mammary hormone-independent tumors in nude mice by inoculating epithelial C4-HD cells expressing a constitutively active form of AKT (myristoilated AKT1). These results indicate that the activation of PI3K/AKT pathway is critical in the generation of an autonomous tumor, and that paracrine signals derived from the tumor microenvironment accompany hormone-independent tumor growth.