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Inflammatory conversion of quiescent osteoblasts by metastatic breast cancer cells through pERK1/2 aggravates cancer-induced bone destruction.

Authors :
Back, Jungho
Nguyen, Minh Nam
Li, Lu
Lee, Saelim
Lee, Inkyu
Chen, Fancheng
Gillinov, Lauren
Chung, Yeon-Ho
Alder, Kareme D.
Kwon, Hyuk-Kwon
Yu, Kristin E.
Dussik, Christopher M.
Hao, Zichen
Flores, Michael J.
Kim, Yoseph
Ibe, Izuchukwu K.
Munger, Alana M.
Seo, Sung Wook
Lee, Francis Y.
Source :
Bone Research; 9/29/2021, Vol. 9 Issue 1, p1-14, 14p
Publication Year :
2021

Abstract

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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
20954700
Volume :
9
Issue :
1
Database :
Complementary Index
Journal :
Bone Research
Publication Type :
Academic Journal
Accession number :
152710018
Full Text :
https://doi.org/10.1038/s41413-021-00158-w