Laboratory Models for Investigating Breast Cancer Therapy Resistance and Metastasis

While numerous therapies are highly efficacious in early-stage breast cancers and in particular subsets of breast cancers, therapeutic resistance and metastasis unfortunately arise in many patients. In many cases, tumors that are resistant to standard of care therapies, as well as tumors that have metastasized, are treatable but incurable with existing clinical strategies. Both therapy resistance and metastasis are multi-step processes during which tumor cells must overcome diverse environmental and selective hurdles. Mechanisms by which tumor cells achieve this are numerous and include acquisition of invasive and migratory capabilities, cell-intrinsic genetic and/or epigenetic adaptations, clonal selection, immune evasion, interactions with stromal cells, entering a state of dormancy or senescence, and maintaining self-renewal capacity. To overcome therapy resistance and metastasis in breast cancer, the ability to effectively model each of these mechanisms in the laboratory is essential. Herein we review historic and the current state-of-the-art laboratory model systems and experimental approaches used to investigate breast cancer metastasis and resistance to standard of care therapeutics. While each model system has inherent limitations, they have provided invaluable insights, many of which have translated into regimens undergoing clinical evaluation. We will discuss the limitations and advantages of a variety of model systems that have been used to investigate breast cancer metastasis and therapy resistance and outline potential strategies to improve experimental modeling to further our knowledge of these processes, which will be crucial for the continued development of effective breast cancer treatments.