Inflammatory conversion of quiescent osteoblasts by metastatic breast cancer cells through pERKl/2 aggravates cancer-induced bone destruction  

作　　者：Jungho Back Minh Nam Nguyen Lu Li Saelim Lee Inkyu Lee Fancheng Chen Lauren Gillinov Yeon-Ho Chung Kareme D.Alder Hyuk-Kwon Kwon Kristin E.Yu Christopher M.Dussik Ziehen Hao Michael J.Flores Yoseph Kim Izuchukwu K.Ibe Alana M.Munger Sung Wook Seo Francis Y.Lee 

机构地区：[1]Department of Orthopaedics&Rehabilitation,Yale University,School of Medicine,New Haven,CT,USA [2]Research Center for Genetics and Reproductive Health,School of Medicine,Vietnam National University Ho Chi Minh City,Linh Trung Ward,Thu Due District,Ho Chi Minh City,Vietnam [3]Department of Rehabilitation Medicine,Renji Hospital,School of Medicine,Shanghai JiaoTong University,Shanghai,China [4]College of Medicine,Dankook University,Cheonan,Republic of Korea [5]Department of Life Science,Chung-Ang University,Seoul,Republic of Korea [6]Shanghai Medical College,Fudan University,Shanghai City,China [7]Department of Emergency&Trauma,Changhai Hospital,Navy Medical University,Shanghai,China [8]Biomedical Engineering,Johns Hopkins University,Baltimore,MD,USA [9]Department of Orthopedic Surgery,Samsung Medical Center,Sungkyunkwan University School of Medicine,Seoul,Gangnam-gu,Republic of Korea

出　　处：《Bone Research》2021年第4期557-570,共14页骨研究（英文版）

基　　金：This work was supported by AR056246(F.Y.L.),AR068353(F.Y.L.),and CA203011(F.Y.L).

摘　　要：Disruption of bone homeostasis caused by metastatic osteolytic breast cancer cells increases inflammatory osteolysis and decreases bone formation,thereby predisposing patients to pathological fracture and cancer growth.Alteration of osteoblast function induces skeletal diseases due to the disruption of bone homeostasis.We observed increased activation of pERK1/2 in osteolytic breast cancer cells and osteoblasts in human pathological specimens with aggressive osteolytic breast cancer metastases.We confirmed that osteolytic breast cancers with high expression of pERK1/2 disrupt bone homeostasis via osteoblastic ERK1/2 activation at the bone-breast cancer interface.The process of inflammatory osteolysis modulates ERK1/2 activation in osteoblasts and breast cancer cells through dominant-negative MEK1 expression and constitutively active MEK1 expression to promote cancer growth within bone.Trametinib,an FDA-approved MEK inhibitor,not only reduced breast cancer-induced bone destruction but also dramatically reduced cancer growth in bone by inhibiting the inflammatory skeletal microenvironment.Taken together,these findings suggest that ERK1/2 activation in both breast cancer cells and osteoblasts is required for osteolytic breast cancer-induced inflammatory osteolysis and that ERK1/2 pathway inhibitors may represent a promising adjuvant therapy for patients with aggressive osteolytic breast cancers by altering the shared cancer and bone microenvironment.

关 键 词：PERK1/2 breast HOMEOSTASIS 

分 类 号：R737.9[医药卫生—肿瘤]