title: Gut-derived serotonin induced by depression promotes breast cancer bone metastasis through the RUNX2/PTHrP/RANKL pathway in mice.
abstract: Breast cancer metastasizes to the bone in a majority of patients with advanced disease resulting in bone destruction. The underlying mechanisms are complex, and both processes are controlled by an interaction between locally and systemically derived signals. Clinically, breast cancer patients with depression have a higher risk of bone metastasis, yet the etiology and mechanisms are yet to be elucidated. MDA‑MB‑231 breast cancer cells were used to establish a bone metastasis model by using intracardiac injection in nude mice. Chronic mild stress (CMS) was chosen as a model of depression in mice before and after inoculation of the cells. Knockdown of the RUNX‑2 gene was performed by transfection of the cells with shRNA silencing vectors against human RUNX‑2. A co‑culture system was used to test the effect of the MDA‑MB‑231 cells on osteoclasts and osteoblasts. RT‑PCR and western blotting were used to test gene and protein expression, respectively. We confirmed that depression induced bone metastasis by promoting osteoclast activity while inhibiting osteoblast differentiation. Free serotonin led to an increase in the expression of RUNX2 in breast cancer cells (MDA‑MB‑231), which directly inhibited osteoblast differentiation and stimulated osteoclast differentiation by the PTHrP/RANKL pathway, which caused bone destruction and formed osteolytic bone lesions. Additionally, the interaction between depression and breast cancer cells was interrupted by LP533401 or RUNX2 knockdown. In conclusion, depression promotes breast cancer bone metastasis partly through increasing levels of gut‑derived serotonin. Activation of RUNX2 in breast cancer cells by circulating serotonin appears to dissociate coupling between osteoblasts and osteoclasts, suggesting that the suppression of gut‑derived serotonin decreases the rate of breast cancer bone metastasis induced by depression.
authors.affiliation: Department of Orthopedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Yuzhong, Chongqing 400010, P.R. China.
authors.forename: Jian-Chun
authors.initials: JC
authors.lastname: Zong
authors.affiliation: Department of Orthopedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Yuzhong, Chongqing 400010, P.R. China.
authors.forename: Xing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Orthopedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Yuzhong, Chongqing 400010, P.R. China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Orthopedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Yuzhong, Chongqing 400010, P.R. China.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Orthopedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Yuzhong, Chongqing 400010, P.R. China.
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Orthopedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Yuzhong, Chongqing 400010, P.R. China.
authors.forename: Liang-Jun
authors.initials: LJ
authors.lastname: Yin
authors.affiliation: Key Laboratory for Biochemistry and Molecular Pharmacology of Chongqing Medical University, Yuzhong, Chongqing 400016, P.R. China.
authors.forename: Bai-Cheng
authors.initials: BC
authors.lastname: He
authors.affiliation: Department of Orthopedic Surgery, The Second Affiliated Hospital, Chongqing Medical University, Yuzhong, Chongqing 400010, P.R. China.
authors.forename: Zhong-Liang
authors.initials: ZL
authors.lastname: Deng
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000556:secondary*; D001943:Breast Neoplasms / Q000473:pathology*; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D003863:Depression / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000473:pathology; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012701:Serotonin / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013315:Stress, Psychological / Q000150:complications / Q000378:metabolism; D014162:Transfection
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D044162:Parathyroid Hormone-Related Protein; D053245:RANK Ligand; D034741:RNA, Small Interfering; D012701:Serotonin