*3.1.3 Breast cancer*

In breast cancer, the Hippo-YAP pathway was controlled by a ROR1-HER3- LncRNA signaling axis to govern bone metastases [110]. Both osteoclastic miR-214/ TNF receptor-associated factor-3 (TRAF-3) pathway and dysregulated miR-124/ IL-11 axis were devoted to the understanding of breast cancer metastases to the bone [111, 112]. A study pointed to a concept in which cancer-derived miR-218 impairs osteoblast function by directly targeting collagen type I alpha 1 chain (COL1A1) and regulating inhibin βA expression [113]. miR-125b may reduce the effect of hypoxiainducible factor 1 alpha subunit (HIF1A), which is known to enhance metastatic spread by upregulating prostaglandin-endoperoxide synthase 2 (PTGS2) [114]. To investigate the influence of miR-429 on the metastatic bone environment in vivo, Zhang et al. created an orthotopic bone degradation model and a left ventricle implantation paradigm. The levels of V-crk sarcoma virus CT10 oncogene homologlike (CrkL) and MMP-9 were negatively influenced by miR-429 [115]. Exosomal miR-21 generates from breast cancer cells promotes osteoclastogenesis by modulating the levels of the protein programmed cell death 4 (PDCD4). Furthermore, the amount of miR-21 in breast cancer patients with bone metastases is considerably greater in serum exosomes [116]. Exosomal miR-19a and integrin-binding sialoprotein (IBSP) are highly increased and secreted from bone-tropic estrogen receptor-positive (ER+) breast cancer cells, resulting in a milieu conducive to colonization in the bone [117]. Teng et al. identified many key lncRNAs such as lncRNA RP11-317-J19.1 related to bone metastasis in breast cancer [122]. By influencing the miR-1273 g-3p/BMP3 axis, LncRNA SNHG3 regulates BMSC osteogenic development in breast cancer bone metastases [118].

In breast cancer, the level of DNA methylation is increased to further regulate Wwox, following to stimulate HGF/Met receptor signaling and E-cadherin, downregulating Twist transactivation, leading to bone metastasis [119].
