Abstract 1419: Role of p70S6K in breast cancer recurrence

Abstract

Abstract In Early Breast Cancer (EBC) a single dose of intraoperative radiotherapy with TARGIT (Targeted Intraoperative RadioTherapy) protocol is as effective as the standard therapy in the control of local recurrences (Vaidya et al. Lancet, 376: 91-102, 2010). We recently demonstrated that TARGIT treatment affects the tumor microenvironment, after breast conserving surgery, by altering the local production of several growth factors and cytokines. Eventually, these changes in the proteomic profile, result in a lower activation of the p70S6K pathway in breast cancer cells (Belletti et al. CCR, 14: 1325-32, 2008). To dissect the role of p70S6K in breast cancer cells proliferation, motility and invasion, we generated genetically modified human breast cancer cell lines expressing specific shRNA or carrying a dominant negative form of p70S6K (p70KR) and tested their ability to grow and migrate, first in vitro then in vivo. Growth curve experiments on MDA MB 231 and MDA MB 453 mammary carcinoma cells, demonstrated that expression of the p70KR mutant slightly reduced the growth rate of these cells. The same cells have been also characterized for their ability to migrate in 2D- and 3D-contexts, in response to the wound fluids harvested from EBC patients as chemoattractants, showing that p70KR reduced their ability to invade. Next, we moved to an in vivo model to evaluate more in detail the involvement of p70S6K in the local recurrence of breast cancer. To this aim, parental or p70S6K genetically modified breast cancer cells have been injected in female nude mice mammary fat pads. Two weeks later, the tumor was removed by surgical excision and the mice observed for the appearance of recurrences. Macroscopic and histo-pathological examination of the primary tumors revealed that despite formation of similar masses, only tumors derived from parental cells displayed lymph-vascular invasion. More importantly, only mammary pads injected with parental cells developed recurrent disease and, at pathological analysis, displayed nodal metastasis. Altogether these data highlight a crucial function of p70S6K in the formation of local recurrence in breast cancers, and support the hypothesis that, in EBC patients, an anti-p70S6K specific therapy may be useful for the prevention of local recurrences. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1419. doi:10.1158/1538-7445.AM2011-1419