| Autor: |
Wright LE; Department of Medicine, Division of Endocrinology, Indiana University, Indianapolis, IN, USA., Harhash AA; Department of Medicine, Division of Endocrinology, Indiana University, Indianapolis, IN, USA., Kozlow WM; Department of Internal Medicine, Division of Endocrinology, University of Virginia, Charlottesville, VA, USA., Waning DL; Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA, USA., Regan JN; Department of Medicine, Division of Endocrinology, Indiana University, Indianapolis, IN, USA., She Y; Department of Medicine, Division of Endocrinology, Indiana University, Indianapolis, IN, USA., John SK; Department of Medicine, Division of Endocrinology, Indiana University, Indianapolis, IN, USA., Murthy S; Department of Medicine, Division of Endocrinology, Indiana University, Indianapolis, IN, USA., Niewolna M; Department of Medicine, Division of Endocrinology, Indiana University, Indianapolis, IN, USA., Marks AR; Department of Physiology, Columbia University, New York, NY, USA., Mohammad KS; Department of Medicine, Division of Endocrinology, Indiana University, Indianapolis, IN, USA., Guise TA; Department of Medicine, Division of Endocrinology, Indiana University, Indianapolis, IN, USA. |
| Abstrakt: |
Aromatase inhibitors (AIs) cause muscle weakness, bone loss, and joint pain in up to half of cancer patients. Preclinical studies have demonstrated that increased osteoclastic bone resorption can impair muscle contractility and prime the bone microenvironment to accelerate metastatic growth. We hypothesized that AI-induced bone loss could increase breast cancer progression in bone and exacerbate muscle weakness associated with bone metastases. Female athymic nude mice underwent ovariectomy (OVX) or sham surgery and were treated with vehicle or AI (letrozole; Let). An OVX-Let group was then further treated with bisphosphonate (zoledronic acid; Zol). At week three, trabecular bone volume was measured and mice were inoculated with MDA-MB-231 cells into the cardiac ventricle and followed for progression of bone metastases. Five weeks after tumor cell inoculation, tumor-induced osteolytic lesion area was increased in OVX-Let mice and reduced in OVX-Let-Zol mice compared to sham-vehicle. Tumor burden in bone was increased in OVX-Let mice relative to sham-vehicle and OVX-Let-Zol mice. At the termination of the study, muscle-specific force of the extensor digitorum longus muscle was reduced in OVX-Let mice compared to sham-vehicle mice, however, the addition of Zol improved muscle function. In summary, AI treatment induced bone loss and skeletal muscle weakness, recapitulating effects observed in cancer patients. Prevention of AI-induced osteoclastic bone resorption using a bisphosphonate attenuated the development of breast cancer bone metastases and improved muscle function in mice. These findings highlight the bone microenvironment as a modulator of tumor growth locally and muscle function systemically. |
