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Inhibition of breast cancer local relapse by targeting p70S6 kinase activity

Significance Statement

In our paper, after in vitro characterization of the role of p70S6 kinase in breast cancer cells, we generated a mouse model of EBC in which we recapitulated the disease course and the therapeutic approaches used in clinic. Using this in vivo model we have established the role of p70S6 kinase in tumor growth and, more importantly, in local recurrence formation. Moreover, our data collected in specimens from EBC patients undergone lumpectomy first and surgical widening to clear surgical margins in a second time, confirmed that p70S6 kinase activity is induced by surgery, also in human disease. The molecular mechanism by which p70S6 kinase is able to elicit cell survival and, eventually, breast cancer relapse, relies on a p70S6 kinase/Gli1/Bcl2 signaling axis and is reported in a paper currently in press in Molecular Oncology.

Figure Legend

The picture, a piece by Golnar Adili, reflects the complexity of the breast biology and breast cancer.

“A Thousand Pages of Chest in a Thousand Pages of Mirro-Pink” 2011 – Eight Sheets of paper, transfer, beeswax.

Inhibition of breast cancer local relapse by targeting p70S6 kinase activity- Global Medical Discovery

 

 

 

 

 

 

 

 

 

 

 

 

Segatto I, Berton S, Sonego M, Massarut S, D’Andrea S, Perin T, Fabris L, Armenia J, Rampioni G, Lovisa S, Schiappacassi M, Colombatti A, Bristow RG,Vecchione A, Baldassarre G, Belletti B.

J Mol Cell Biol. 2013 Dec;5(6):428-31.

Division of Experimental Oncology 2, CRO, National Cancer Institute, Aviano 33081, Italy.

Abstract

 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. The ribosomal protein p70S6 kinase 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 used in vitro and in vivo models of breast cancer to investigate whether interfering with p70S6 kinase activity, either genetically or pharmacologically, could suppress disease relapse. Moreover, relevance of p70S6 kinase activity in human pathology has been evaluated in breast cancer specimens from EBC patients.

Interfering with p70S6 kinase activity strongly impaired breast cancer cell survival in vitro and local relapse in vivo. Peri-operative treatment using specific pharmacological inhibition of p70S6 kinase  was sufficient to reduce by 83% the rate of local recurrence. The significance of our results was confirmed in human EBC specimens, proving that p70S6 kinase activity is robustly induced by surgery, also in human patients.

Taken together, our results provide a biological rationale for a novel peri-operative treatment targeting p70S6 kinase pathway, directed to compensating the harmful consequences of surgery and to restraining local recurrence of breast cancer.

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