Abstract 172: 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

Abstract

Abstract 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 α or ≤ 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 PKCα induced alterations in LM3 in vitro behavior that could be associated with tumor progression. In this sense, PKCα increased proliferation and motility (wound coverage: 69.3±8.3% vs 41.2±5.1% in control cells p<0.05) of the transfected LM3 cells. Interestingly, at the same time PKCα sensitized LM3 cells to ATRA treatment as evidenced by a significant reduction in both parameters. Upon othotopic inoculation into syngeneic mice LM3-PKCα 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-PKCα treated or not respectively p<0.05). On the contrary PKC ≤ overexpression did not affect LM3 cells behavior either in vitro or in vivo. LM3 cells response to ATRA was not modulated by PKC∈ either. However, through a RARE-luciferase gene reporter assay, we could determine that the overexpression of PKC∈ increased the activity of the retinoic acid receptors. Our results show that PKCα overexpression induced a more aggressive phenotype but also conferred ATRA sensitivity to mammary tumor cells. On the other side high PKC∈ 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 PKCα expression levels. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 172. doi:1538-7445.AM2012-172