Breast cancer at bone metastatic sites: recent discoveries and treatment targets

Abstract

Breast carcinoma is the most common cancer of women. Bones are often involved with breast carcinoma metastases with the resulting morbidity and reduced quality of life. Breast cancer cells arriving at bone tissues mount supportive microenvironment by recruiting and modulating the activity of several host tissue cell types including the specialized bone cells osteoblasts and osteoclasts. Pathologically activated osteoclasts produce osteolytic lesions associated with bone pain, pathological fractures, cord compression and other complications of metastatic breast carcinoma at bone. Over the last decade there has been enormous growth of knowledge in the field of osteoclasts biology both in the physiological state and in the tumor microenvironment. This knowledge allowed the development and implementation of several targeted therapeutics that expanded the armamentarium of the oncologists dealing with the metastases-associated osteolytic disease. While the interactions of cancer cells with resident bone cells at the established metastatic gross lesions are well-studied, the preclinical events that underlie the progression of disseminated tumor cells into micrometastases and then into clinically-overt macrometastases are just starting to be uncovered. In this review, we discuss the established information and the most recent discoveries in the pathogenesis of osteolytic metastases of breast cancer, as well as the corresponding investigational drugs that have been introduced into clinical development.

Fig. 1

Schematics demonstrating the interactions between invading tumor cells and bone cells during breast cancer metastasis to bone. Red arrows indicate the effects of tumor cells on bone cells; blue arrows depict the reciprocal effects of bone cells on tumor cells

Fig. 2

Different models of breast cancer dormancy: In the single-cell model (left), cells detached from indolent breast carcinomas lodge at the sites of future metastases and remain quiescent in a state of prolonged survival. In the micro-metastasis model (right), cells detached from aggressive carcinomas lodge at the sites of future metastases and form microscopic tumor foci that have a balanced state of proliferation and apoptosis

Fig. 3

Schematics of the main therapeutic targets explored for treatment of breast cancer metastases to bone. TCE 9908 is a CXCR4 inhibitor, Denosumab is a fully humanized monoclonal antibody against RANKL, Dasatinib is an inhibitor of multiple tyrosine kinases including the Src family, NBPs are nitrogen-containing bisphosphonates. The main intracellular signalling molecules in osteoclasts are represented by white ovals while transcription factors are represented by green ovals