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.

Dormancy in breast cancer

“…It appears that dormant cancer cells can persist either by completely withdrawing from the cell cycle (mitotic arrest) or by continuing to proliferate at a slow rate that is counterbalanced by cell death (Figure 1). 38,39 These two types of dormancy are not mutually exclusive; both forms of latency could coexist in the entire population of DTC of a particular cancer patient.…”

“…Hussein and Komarova hypothesized that indolent breast cancers might fit into the single-cell dormancy model, while more aggressive diseases are linked to the micrometastatic dormancy model. 39 Indeed, in a series of experiments, Barkan et al demonstrated that more aggressive basal-type cell lines, such as MDA-MB-231, proliferated readily, while estrogen receptor (ER)-positive MCF7 remained in a state of mitotic arrest, potentially linking the dormancy type associated with arrested growth with the less aggressive disease phenotype.…”

Subtrochanteric Fracture as First Sign of Metastatic Breast Cancer: Case Presentation

“…Skeletalrelated events (SREs) frequently complicate a bone metastasis and depending on the location of the dissemination they can represent spinal compressions, pathological bone fractures, bone marrow infiltration or malignancy hypercalcemia [8]. Secondary bony determinations are characterized by osteolytic lesions produced by pathologically activated osteoclasts [9]. This activity usually causes a substantial amount of pain, creating the premises for diagnosing the tumor.…”

Breast Cancer Genomics

“…At present, there is no defi nite answer to the question of which model best represents tumor dormancy in breast cancer. Hussein and Komarova hypothesized that indolent breast cancers might fi t into the single-cell dormancy model, while more aggressive diseases are linked to the micrometastatic dormancy model [ 229 ]. Indeed, in a series of experiments, Barkan et al demonstrated that more aggressive basal-type cell lines, such as MDA-MB-231, proliferated readily, while estrogen receptor (ER)-positive MCF7 remained in a state of mitotic arrest, potentially linking the dormancy type associated with arrested growth with the less aggressive disease phenotype [ 242 ].…”