Pharmacological Inhibition of the Skeletal IKKβ Reduces Breast Cancer-Induced Osteolysis.

Autor:	Marino, Silvia, Bishop, Ryan T., Mollat, Patrick, Idris, Aymen I.
Předmět:	BREAST cancer treatment PHARMACOLOGY BONE metastasis BONE remodeling OSTEOBLASTS OSTEOBLAST metabolism ANIMAL experimentation APOPTOSIS BONE resorption BONE growth BONE tumors BREAST tumors CELL differentiation CELL lines CELLULAR signal transduction COMPUTED tomography CULTURE media (Biology) MACROPHAGES METASTASIS MICE PROTEOLYTIC enzymes RESEARCH funding TRANSFERASES
Zdroj:	Calcified Tissue International; Aug2018, Vol. 103 Issue 2, p206-216, 11p
Abstrakt:	IKKβ has previously been implicated in breast cancer bone metastasis and bone remodelling. However, the contribution of IKKβ expressed by bone cells of the tumour microenvironment to breast cancer-induced osteolysis has yet to be investigated. Here, we studied the effects of the verified selective IKKβ inhibitors IKKβIII or IKKβV on osteoclast formation and osteoblast differentiation in vitro and in vivo, human and mouse breast cancer cells' support for osteoclast formation and signalling in vitro and osteolysis ex vivo and in immunocompetent mice after supracalvarial injection of human MDA-MB-231 conditioned medium or intra-cardiac injection of syngeneic 4T1 breast cancer cells. Pre-treatment with IKKβIII or IKKβV prior to exposure to tumour-derived factors from human and mouse breast cancer cell lines protected against breast cancer-induced osteolysis in two independent immunocompetent mouse models of osteolysis and the ex vivo calvarial bone organ system. Detailed functional and mechanistic studies showed that direct inhibition of IKKβ kinase activity in osteoblasts and osteoclasts was associated with significant reduction of osteoclast formation, enhanced osteoclast apoptosis and reduced the ability of osteoblasts to support osteoclastogenesis in vitro. When combined with previous findings that suggest NFκB inhibition reduces breast cancer tumorigenesis and metastasis our present findings have an important clinical implication on raising the possibility that IKKβ inhibitors, as bone anabolics, osteoclast inhibitors as well as anti-metastatic agents, may have advantages over anti-osteoclasts agents in the treatment of both skeletal and non-skeletal complications associated with metastatic breast cancer. [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
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