Bone Research ( IF 12.7 ) Pub Date : 2021-09-29 , DOI: 10.1038/s41413-021-00158-w Jungho Back 1 , Minh Nam Nguyen 1, 2 , Lu Li 1, 3 , Saelim Lee 1, 4 , Inkyu Lee 1, 5 , Fancheng Chen 1, 6 , Lauren Gillinov 1 , Yeon-Ho Chung 1 , Kareme D Alder 1 , Hyuk-Kwon Kwon 1 , Kristin E Yu 1 , Christopher M Dussik 1 , Zichen Hao 1, 7 , Michael J Flores 1 , Yoseph Kim 8 , Izuchukwu K Ibe 1 , Alana M Munger 1 , Sung Wook Seo 9 , Francis Y Lee 1
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.
中文翻译:
转移性乳腺癌细胞通过 pERK1/2 对静止成骨细胞的炎症转化加剧了癌症诱导的骨破坏
转移性溶骨性乳腺癌细胞引起的骨稳态破坏增加了炎症性骨质溶解并减少了骨形成,从而使患者易患病理性骨折和癌症生长。由于骨稳态的破坏,成骨细胞功能的改变会诱发骨骼疾病。我们观察到侵袭性溶骨性乳腺癌转移的人类病理标本中溶骨性乳腺癌细胞和成骨细胞中 pERK1/2 的激活增加。我们证实,pERK1/2 高表达的溶骨性乳腺癌通过骨-乳腺癌界面处的成骨细胞 ERK1/2 激活破坏骨稳态。炎症性骨溶解过程通过显性失活 MEK1 表达和组成型活性 MEK1 表达调节成骨细胞和乳腺癌细胞中的 ERK1/2 激活,从而促进骨内癌症的生长。Trametinib 是一种 FDA 批准的 MEK 抑制剂,它不仅可以减少乳腺癌引起的骨质破坏,还可以通过抑制炎症性骨骼微环境显着减少骨骼中的癌症生长。综上所述,这些发现表明,乳腺癌细胞和成骨细胞中的 ERK1/2 激活是溶骨性乳腺癌诱导的炎症性骨质溶解所必需的,并且 ERK1/2 通路抑制剂可能通过改变共享的癌症和骨骼微环境。Trametinib 是一种 FDA 批准的 MEK 抑制剂,它不仅可以减少乳腺癌引起的骨质破坏,还可以通过抑制炎症性骨骼微环境显着减少骨骼中的癌症生长。综上所述,这些发现表明,乳腺癌细胞和成骨细胞中的 ERK1/2 激活是溶骨性乳腺癌诱导的炎症性骨质溶解所必需的,并且 ERK1/2 通路抑制剂可能通过改变共享的癌症和骨骼微环境。Trametinib 是一种 FDA 批准的 MEK 抑制剂,它不仅可以减少乳腺癌引起的骨质破坏,还可以通过抑制炎症性骨骼微环境显着减少骨骼中的癌症生长。综上所述,这些发现表明,乳腺癌细胞和成骨细胞中的 ERK1/2 激活是溶骨性乳腺癌诱导的炎症性骨质溶解所必需的,并且 ERK1/2 通路抑制剂可能通过改变共享的癌症和骨骼微环境。