Role of p70S6K and STAT3 signaling pathways in breast cancer recurrence

For early breast cancer (EBC) patients, local relapse represents what mostly influences disease outcome. Surgery itself and the consequent process of wound healing have been proposed to stimulate local recurrences via pathway(s) still to be clarified. Notably, 90% of local recurrences occur at or close to the same quadrant of the primary cancer. p70S6K and STAT3 pathways have been implicated in breast cancer cell response to post-surgical inflammation, supporting the hypothesis that they may be crucial also for breast cancer recurrence. The results of this PhD thesis show that interfering with p70S6K activity strongly impaired breast cancer cell survival in vitro and local relapse in vivo. Peri-operative treatment using specific pharmacological inhibition of p70S6K1 was sufficient to reduce by 83% the rate of local recurrence. The significance of our results was confirmed in human EBC specimens, proving that p70S6K activity is consistently increased by surgery, also in human patients. Our study also highlighted that surgical fluids very efficiently activated STAT3 and that STAT3 activity was necessary for the survival and growth of tumor initiating cells. Taken together, our results show that p70S6K and STAT3 pathway are strongly involved in the promotion of the survival of residual tumor cells in the breast microenvironment. Moreover, we demonstrate that p70S6K is an important regulator of breast cancer progression and could be used as target to restrain recurrent disease and to improve clinical outcomes in EBC patients. Finally, we show that STAT3 impinges on breast cancer stem cell phenotype upon WF stimulation and its precise role in the insurgence of local recurrence is currently under investigation.