Molecular Mechanisms of Breast Cancer Metastasis to the Lung: Clinical and Experimental Perspectives

Abstract

Breast cancer is the most commonly diagnosed cancer in women worldwide, and >90% of breast cancer-related deaths are associated with metastasis. Breast cancer spreads preferentially to the lung, brain, bone and liver; termed organ tropism. Current treatment methods for metastatic breast cancer have been ineffective, compounded by the lack of early prognostic/predictive methods to determine which organs are most susceptible to developing metastases. A better understanding of the mechanisms that drive breast cancer metastasis is crucial for identifying novel biomarkers and therapeutic targets. Lung metastasis is of particular concern as it is associated with significant patient morbidity and a mortality rate of 60-70%. This review highlights the current understanding of breast cancer metastasis to the lung, including discussion of potential new treatment approaches for development.

Keywords: breast cancer; exosomes; lung metastasis; pre-metastatic niche; targeted therapies; tumor secreted factors.

Figure 1

The underlying mechanisms that dictate the organ colonized by breast cancer are complex and influenced by many factors. Breast primary tumors regulate and prime the lung for metastasis by the secretion of tumor-derived exosomes (TDEs) and tumor-derived secreted factors (TDSFs), which target the bone marrow for recruitment of bone marrow-derived cells (BMDCs) to lung in order to induce changes in the extracellular matrix (ECM) that are conducive for metastasis. Release of TDSFs from the primary tumor are often regulated by stromal cells that compose the tumor microenvironment including cancer associated fibroblasts (CAFs) or environmental stimuli such as hypoxia.