Radiotherapy-induced miR-223 prevents relapse of breast cancer by targeting the EGF pathway

• Published in: Oncogene Vol. 35; no. 37; pp. 4914 - 4926
• Main Authors: Fabris, L, Berton, S, Citron, F, D'Andrea, S, Segatto, I, Nicoloso, M S, Massarut, S, Armenia, J, Zafarana, G, Rossi, S, Ivan, C, Perin, T, Vaidya, J S, Avanzo, M, Roncadin, M, Schiappacassi, M, Bristow, R G, Calin, G, Baldassarre, G, Belletti, B
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.09.2016; Nature Publishing Group
• Subjects: 13/109; 13/95; 14; 14/19; 38; 38/61; 38/90; 631/67/1347; 64/60; 82/80; 96/1; 96/95; Analysis; Animals; Apoptosis; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Breast Neoplasms - radiotherapy; Cancer prevention; Cell Biology; Cell Line, Tumor; Cell Proliferation - radiation effects; Epidermal Growth Factor - genetics; Epidermal growth factors; ErbB Receptors - genetics; Female; Gene Expression Regulation, Neoplastic; Human Genetics; Humans; Internal Medicine; Lumpectomy; Medicine; Medicine & Public Health; Mice; MicroRNAs; MicroRNAs - genetics; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - pathology; Neoplasm Recurrence, Local - radiotherapy; Oncology; Original; original-article; Prevention; Radiation therapy; Radiotherapy; Recurrence; Recurrence (Disease); Scars; Signal Transduction - radiation effects; Tumor removal; Wound Healing
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2016.23

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.