Abstract P1-05-11: Breaking “vicious cycle”? The role of miR-223 in breast cancer metastasis to bone

Abstract

Abstract The “seed and soil” theory of metastasis was proposed by Stephen Paget in 1889. The theory suggests that bone acts as a fertile environment (soil) for cancer cells (seeds) colonization and growth. The theory successfully explains how bone and breast cancer cells interact to support breast cancer cell growth within the bone microenvironment.Breast cancer cells that metastasize to bone secrete growth factors and cytokines into the bone microenvironment that promote the production of receptor activator nuclear factor κ β ligand (RANKL), which, in turn, leads to osteoclast formation. The osteoclasts then cause bone resorption and the subsequent release of growth factors, include transforming growth factor-beta (TGF-β), bone morphogenetic proteins (BMPs), insulin-like growth factors (IGFs), fibroblast growth factors (FGFs), and platelet-derived growth factors (PDGF) into the bone microenvironment, which further stimulate the growth of breast cancer cells. Growth factors and cytokines produced by both breast cancer cells and bone cells result in a “vicious cycle” of bone breakdown: factors released from the bone promote breast cancer cell proliferation, which leads to more bone loss, and the subsequent release of more growth factors from the bone. The concept of the “vicious cycle” was proposed in 1997 by Mundy and Guise. Currently, the “vicious cycle” model provides the best description of our understanding of the interaction between breast cancer and bone. We found in miR-223 knockout mice, the bone volume of lowe limb bones is significantly lower than C57BL/6 mice (wild type), the osteoclastic resorption is more severe in miR-223 knockout mice according to H&E sections. Then, we hypothesized miR-223 may inhibit osteoclast formation. In vitro study, We found miR-223 can suppress RANKL activating osteocalst formation by targeting NF1A protein. These results indicated miR-223 may disturb the establishment of osteolytic lesion, which may destroy the “soil” in bone microenvironment. Besides, we also found in miR-223 knockout mice, the IGF-1R is over expressed and the PI3K-Akt pathway was excessively activated. miR-223 up-regulation can inhibit MDA-231 cell proliferation but enhance apoptosis, which may destroy the “seed” in bone microenvironment. In conclusion, we hypothesized that miR-223 may break the “vicious cycle” and suppress breast cancer metastasis to bone. Citation Format: Zhen Shan, Wen Li, Ying Lin, Huijuan Zeng, Yunling Qi, Zefei Lin, Yuanjian Fan. Breaking “vicious cycle”? The role of miR-223 in breast cancer metastasis to bone [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-05-11.