In early
breast cancer, local relapses represent a determinant and not simply an
indicator of risk for distant relapse and death. Notably, 90% of local recurrences occur at or close to the same quadrant of the primary
cancer. Relevance of PI3K/mTOR/
p70S6K signaling in breast
tumorigenesis is very well documented. However, the pathway/s involved in the process of
breast cancer local relapse are not well understood. The
ribosomal protein p70S6K has been implicated in
breast cancer cell response to post-surgical
inflammation, supporting the hypothesis that it may be crucial also for
breast cancer recurrence. Here, we show that
p70S6K activity is required for the survival of
breast cancer cells challenged in "hostile" microenvironments. We found that impairment of
p70S6K activity in
breast cancer cells strongly decreased their
tumor take rate in nude mice. In line with this observation, if cells were challenged to grow in anchorage independence or in clonogenic assay, growth of colonies was strongly dependent on an intact
p70S6K signaling. This in vitro finding was particularly evident when
breast cancer cells were grown in the presence of
wound fluids harvested following surgery from
breast cancer patients, suggesting that the stimuli present in the post-surgical setting at least partially relied on activity of
p70S6K to stimulate
breast cancer relapse. From a mechanistic point of view, our results indicated that
p70S6K signaling was able to activate Gli1 and up-regulate the
anti-apoptotic protein Bcl2, thereby activating a survival response in
breast cancer cells challenged in hostile settings. Our work highlights a previously poorly recognized function of
p70S6K in preserving
breast cancer cell survival, which could eventually be responsible for local relapse and opens the way to the design of new and more specific
therapies aiming to restrain the deleterious effects of
wound response.