Joan E Lipa1, Wei Qiu, Ning Huang, Benjamin A Alman, Cho Y Pang. 1. Los Angeles, Calif.; and Toronto, Ontario, Canada From the Division of Plastic and Reconstructive Surgery, David Geffen School of Medicine at UCLA, University of California, Los Angeles; the Research Institute, The Hospital for Sick Children; and the Divisions of Orthopedic Surgery and Plastic Surgery, Department of Surgery, and the Department of Physiology, University of Toronto.
Abstract
BACKGROUND: Capsular contracture is the main complication in postmastectomy tissue expander and implant breast reconstruction in patients requiring radiotherapy. There is evidence that the wingless signaling pathway plays a central role in the pathogenesis of fibroproliferation in fibromatosis and hyperplastic skin wounds, involving multiple linked events leading to up-regulation of target genes and fibroproliferation. Here, the authors tested their hypothesis that the wingless signaling pathway may also regulate radiotherapy-induced fibroproliferation in capsular tissue around expanders/implants in breast reconstruction. METHODS: Biopsies of the periprosthetic capsule were obtained from patients undergoing bilateral expander breast reconstruction in which one side was radiated and the other side was not radiated. Capsular biopsies were snap-frozen and stored at -80 degrees C for Western blot assays to determine protein content of phospho-glycogen-synthase-kinase-3beta (phospho-GSK-3beta), total GSK-3beta, beta-catenin, cyclooxygenase-2 (COX-2), and collagen types I and III (n = three to five patients), normalized to beta-actin. Immunostaining for beta-catenin in radiated and nonradiated capsular tissue was also performed. Slides were scanned and analyzed using Zeiss Mirax Scan. RESULTS: The following protein content levels were significantly (p < 0.01) increased in radiated capsule compared with nonradiated capsule: phospho-GSK-3beta (6.7-fold), total GSK-3beta (3.0-fold), beta-catenin (2.3-fold), COX-2 (2.8-fold), and collagen type I (1.6-fold) and type III (1.8-fold). Immunohistochemical staining demonstrated increased fibroblast cytosolic beta-catenin staining and evidence of beta-catenin nuclear translocation in radiated compared with nonradiated capsular tissue. CONCLUSION: Results from this study highlight the importance of the wingless signaling pathway in the pathogenesis of radiation-induced fibroproliferation associated with capsular contracture in expander/implant breast reconstruction.
BACKGROUND: Capsular contracture is the main complication in postmastectomy tissue expander and implant breast reconstruction in patients requiring radiotherapy. There is evidence that the wingless signaling pathway plays a central role in the pathogenesis of fibroproliferation in fibromatosis and hyperplastic skin wounds, involving multiple linked events leading to up-regulation of target genes and fibroproliferation. Here, the authors tested their hypothesis that the wingless signaling pathway may also regulate radiotherapy-induced fibroproliferation in capsular tissue around expanders/implants in breast reconstruction. METHODS: Biopsies of the periprosthetic capsule were obtained from patients undergoing bilateral expander breast reconstruction in which one side was radiated and the other side was not radiated. Capsular biopsies were snap-frozen and stored at -80 degrees C for Western blot assays to determine protein content of phospho-glycogen-synthase-kinase-3beta (phospho-GSK-3beta), total GSK-3beta, beta-catenin, cyclooxygenase-2 (COX-2), and collagen types I and III (n = three to five patients), normalized to beta-actin. Immunostaining for beta-catenin in radiated and nonradiated capsular tissue was also performed. Slides were scanned and analyzed using Zeiss Mirax Scan. RESULTS: The following protein content levels were significantly (p < 0.01) increased in radiated capsule compared with nonradiated capsule: phospho-GSK-3beta (6.7-fold), total GSK-3beta (3.0-fold), beta-catenin (2.3-fold), COX-2 (2.8-fold), and collagen type I (1.6-fold) and type III (1.8-fold). Immunohistochemical staining demonstrated increased fibroblast cytosolic beta-catenin staining and evidence of beta-catenin nuclear translocation in radiated compared with nonradiated capsular tissue. CONCLUSION: Results from this study highlight the importance of the wingless signaling pathway in the pathogenesis of radiation-induced fibroproliferation associated with capsular contracture in expander/implant breast reconstruction.
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