INVESTIGADORES
URTREGER Alejandro Jorge
congresos y reuniones científicas
Título:
Utility of retinoid treatment in the reversion of the malignant phenotype of mammary tumors with alterations in the expression of protein kinase C (PKC) isoforms
Autor/es:
MARIA I. DIAZ BESSONE; DAMIAN E. BERARDI; STÉFANO M. CIRIGLIANO; PAOLA B. CAMPODÓNICO; ELISA D. BAL DE KIER JOFFÉ; LAURA B. TODARO; ALEJANDRO J. URTREGER
Lugar:
Chicago
Reunión:
Congreso; 103rd Annual Meeting of the American Associaton for Cancer Research; 2012
Institución organizadora:
American Associaton for Cancer Research (AACR)
Resumen:
Some of the most promising signaling pathways for breast cancer treatment include the PKC family, involved in proliferation and apoptosis, and the retinoid system mainly involved in differentiation. In this work we have developed a murine model of mammary adenocarcinoma-derived cells (LM3) that overexpress a or d PKC isoforms in order to analyze whether elevated levels of these kinases alter cell sensitivity to retinoid treatment (ATRA). LM3 cells are poorly responsive to ATRA. The overexpression of PKCa induced alterations in LM3 in vitro behavior that could be associated with tumor progression. In this sense, PKCa increased proliferation and motility (wound coverage: 69.3±8.3% vs 41.2±5.1% in control cells) of the transfected LM3 cells. Interestingly, at the same time PKCa sensitized LM3 cells to ATRA treatment as evidenced by a significant reduction in both parameters. Upon othotopic inoculation into syngeneic mice LM3-PKCa cells formed tumors with higher growth rate and metastatic potential than LM3-vector cells. In vivo treatment with an ATRA pellet reduced both the local tumor growth and the number of spontaneous lung metastases (Md [Range]: 9 [0-27] vs 55 [20-75] for LM3-PKCa treated or not respectively). On the contrary PKCd overexpression did not affect LM3 cells behavior either in vitro or in vivo. LM3 cells response to ATRA was not modulated by PKCd either. However, through a RARE-luciferase gene reporter assay, we could determine that the overexpression of PKCd increased the activity of the retinoic acid receptors. Our results show that PKCa overexpression induced a more aggressive phenotype but also conferred ATRA sensitivity to mammary tumor cells. On the other side high PKCd levels increased the activity of retinoid receptors but did not modulate biological cell responses to retinoids. We believe that the use of retinoids may be beneficial in patients with aggressive breast tumors associated with high PKCa expression levels.