title: Radiotherapy-induced miR-223 prevents relapse of breast cancer by targeting the EGF pathway.
abstract: In breast cancer (BC) patients, local recurrences often arise in proximity of the surgical scar, suggesting that response to surgery may have a causative role. Radiotherapy (RT) after lumpectomy significantly reduces the risk of recurrence. We investigated the direct effects of surgery and of RT delivered intraoperatively (IORT), by collecting irradiated and non-irradiated breast tissues from BC patients, after tumor removal. These breast tissue specimens have been profiled for their microRNA (miR) expression, in search of differentially expressed miR among patients treated or not with IORT. Our results demonstrate that IORT elicits effects that go beyond the direct killing of residual tumor cells. IORT altered the wound response, inducing the expression of miR-223 in the peri-tumoral breast tissue. miR-223 downregulated the local expression of epidermal growth factor (EGF), leading to decreased activation of EGF receptor (EGFR) on target cells and, eventually, dampening a positive EGF-EGFR autocrine/paracrine stimulation loop induced by the post-surgical wound-healing response. Accordingly, both RT-induced miR-223 and peri-operative inhibition of EGFR efficiently prevented BC cell growth and reduced recurrence formation in mouse models of BC. Our study uncovers unknown effects of RT delivered on a wounded tissue and prompts to the use of anti-EGFR treatments, in a peri-operative treatment schedule, aimed to timely treat BC patients and restrain recurrence formation.
authors.affiliation: Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Fabris
authors.affiliation: Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy.|Princess Margaret Cancer Centre, Departments of Radiation Oncology and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Berton
authors.affiliation: Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Citron
authors.affiliation: Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy.
authors.forename: S
authors.initials: S
authors.lastname: D'Andrea
authors.affiliation: Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Segatto
authors.affiliation: Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy.|MD Anderson Cancer Center, Department of Experimental Therapeutics, Houston, TX, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Nicoloso
authors.affiliation: Breast Surgery Unit, Department of Oncology and Surgery, CRO Aviano, National Cancer Institute, Aviano, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Massarut
authors.affiliation: Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy.
authors.forename: J
authors.initials: J
authors.lastname: Armenia
authors.affiliation: Princess Margaret Cancer Centre, Departments of Radiation Oncology and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Zafarana
authors.affiliation: MD Anderson Cancer Center, Department of Experimental Therapeutics, Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Rossi
authors.affiliation: MD Anderson Cancer Center, Department of Experimental Therapeutics, Houston, TX, USA.
authors.forename: C
authors.identifier: 0000-0002-4848-0168
authors.initials: C
authors.lastname: Ivan
authors.affiliation: Pathology Unit, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Perin
authors.affiliation: Division of Surgery and Interventional Science, University College London, London, UK.
authors.forename: J S
authors.initials: JS
authors.lastname: Vaidya
authors.affiliation: Medical Physics Unit, Department of Oncology and Radiotherapy, CRO Aviano, National Cancer Institute, Aviano, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Avanzo
authors.affiliation: Radiotherapy Unit, Department of Oncology and Radiotherapy, CRO Aviano,National Cancer Institute, Aviano, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Roncadin
authors.affiliation: Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Schiappacassi
authors.affiliation: Princess Margaret Cancer Centre, Departments of Radiation Oncology and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: R G
authors.initials: RG
authors.lastname: Bristow
authors.affiliation: MD Anderson Cancer Center, Department of Experimental Therapeutics, Houston, TX, USA.
authors.forename: G
authors.initials: G
authors.lastname: Calin
authors.affiliation: Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Baldassarre
authors.affiliation: Division of Experimental Oncology 2, Department of Translational Research, CRO Aviano, National Cancer Institute, Aviano, Italy.
authors.forename: B
authors.identifier: 0000-0003-2249-0285
authors.initials: B
authors.lastname: Belletti
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000528:radiation effects; D004815:Epidermal Growth Factor / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D011878:Radiotherapy; D012008:Recurrence; D015398:Signal Transduction / Q000528:radiation effects; D014945:Wound Healing
chemical_list: D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D035683:MicroRNAs; C525067:MIR223, human; C512478:EGFR protein, human