title: p70S6 kinase mediates breast cancer cell survival in response to surgical wound fluid stimulation.
abstract: 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.
authors.affiliation: Division of Experimental Oncology 2, CRO, National Cancer Institute, Aviano 33081, Italy.
authors.forename: Ilenia
authors.initials: I
authors.lastname: Segatto
authors.affiliation: Division of Experimental Oncology 2, CRO, National Cancer Institute, Aviano 33081, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Berton
authors.affiliation: Division of Experimental Oncology 2, CRO, National Cancer Institute, Aviano 33081, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Sonego
authors.affiliation: Breast Surgery Unit, CRO, National Cancer Institute, Aviano 33081, Italy.
authors.forename: Samuele
authors.initials: S
authors.lastname: Massarut
authors.affiliation: Division of Experimental Oncology 2, CRO, National Cancer Institute, Aviano 33081, Italy.
authors.forename: Linda
authors.initials: L
authors.lastname: Fabris
authors.affiliation: Division of Experimental Oncology 2, CRO, National Cancer Institute, Aviano 33081, Italy.
authors.forename: Joshua
authors.initials: J
authors.lastname: Armenia
authors.affiliation: Breast Surgery Unit, CRO, National Cancer Institute, Aviano 33081, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Mileto
authors.affiliation: Division of Experimental Oncology 2, CRO, National Cancer Institute, Aviano 33081, Italy; Department of Scienze Biologiche e Mediche, MATI Center of Excellence, University of Udine, 33100 Udine, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Colombatti
authors.affiliation: Division of Pathology, University of Rome "La Sapienza", Sant' Andrea Hospital, Rome 00189, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Vecchione
authors.affiliation: Division of Experimental Oncology 2, CRO, National Cancer Institute, Aviano 33081, Italy.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Baldassarre
authors.affiliation: Division of Experimental Oncology 2, CRO, National Cancer Institute, Aviano 33081, Italy. Electronic address: bbelletti@cro.it.
authors.forename: Barbara
authors.initials: B
authors.lastname: Belletti
mesh_terms: D000818:Animals; D001940:Breast / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases
keywords: Breast cancer; Proliferation; Survival; Xenograft; mTOR; p70S6K