title: Bone metastasis in breast cancer: the story of RANK-ligand.
abstract: The primary cellular mechanism responsible for osteolytic bone metastases is osteoclastic activation. Preclinical models have shown that breast cancer cells can produce parathyroid hormone-related protein (PTHrP), and other osteolytic molecules, which stimulate excessive osteoclastic bone resorption and establishment of osteolytic lesions. It has been shown that PTHrP by itself cannot directly induce osteoclastic activation, but it mediates its effect through the transactivation of RANK-ligand (RANKL) gene on stromal and osteoblastic cells. Accordingly RANKL up-regulation has been considered as a prerequisite in virtually all conditions of cancer induced bone destruction. Hence, therapeutic targeting of RANKL seems to be a rational approach to treat or even to prevent the process of bone metastases. In this review, we will focus on the unique patho-physiological aspects related to the evolution of bone metastases in breast cancer, emphasizing the pivotal role of RANKL and some other key molecules in osteoclastic bone resorption. We will discuss the therapeutic interventions using bisphosphonates and RANKL inhibitors in patients with bone metastases and the outcome of this novel approach.
authors.affiliation: Department of Clinical Oncology, Cairo University Hospital, Cairo, Egypt. azimonc@cairocure.com
authors.forename: Hamdy A
authors.initials: HA
authors.lastname: Azim
authors.forename: Nermine S
authors.initials: NS
authors.lastname: Kamal
authors.forename: Hatem A
authors.initials: HA
authors.lastname: Azim
mesh_terms: D000818:Animals; D050071:Bone Density Conservation Agents / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary*; D001862:Bone Resorption; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D004164:Diphosphonates / Q000627:therapeutic use; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D053245:RANK Ligand; C505688:TNFSF11 protein, human