For early breast cancer (EBC) patients local relapse represents what mostly influences disease outcome. Notably, 90% of local recurrences occur at or close to the same quadrant of the primary cancer. Surgery itself and the consequent process of wound healing have been proposed to stimulate local recurrences via pathway(s) still to be clarified. Our previous studies implicated p70S6K pathway in breast cancer cell response to post-surgical inflammation, supporting the hypothesis that it may be crucial also for breast cancer recurrence.

We designed an in vivo experimental model resembling the course of human BC, in which MDA-MB-231 breast cancer cells were bilaterally injected in nude mice mammary fat pads and, when primary tumors were grown, masses were surgically removed under anesthesia. After recovering, mice were followed up to detect appearance of local relapse. Using this model, we dissected the role of p70S6K during breast cancer growth and recurrence by modulating its activity using both genetic and pharmacologic approaches.

Our results showed that p70S6K positively contributed to proliferation and survival programs in breast cancer cell lines. In vivo, the analysis of the impact of p70S6K on primary tumor growth highlighted that a robust p70S6K signaling was required for the initiation of the tumor masses. But, more importantly, interfering with p70S6K activity strongly impaired local relapse. A three-day schedule of peri-operative treatment using specific pharmacological inhibition of p70S6K1 was sufficient to reduce by 83% the rate of local recurrence. We showed that inhibition of p70S6K activity induced apoptosis in cells challenged to survive in a hostile environment, supporting the idea that p70S6K signaling is necessary for the survival of isolated cancer cells in breast microenvironment, following surgery. The significance of our results was confirmed in human EBC specimens, proving that p70S6K activity is robustly induced by surgery, also in human patients.

Taken together, our results provide a biological rationale for peri-operative treatment targeting p70S6K pathway, directed to compensating the harmful consequences of surgery and to restraining local recurrence in early breast cancer patients.

Citation Format: Ilenia Segatto, Stefania Berton, Maura Sonego, Samuele Massarut, Tiziana Perin, Gustavo Baldassarre, Barbara Belletti. p70S6K activity drives local relapse in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B056.