Laboratory Models for Investigating Breast Cancer Therapy Resistance and Metastasis

Abstract

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.

Wnt Signaling in the Breast: From Development to Disease

“…Murine models of breast cancer differ from human breast neoplasms in many ways, including their immune environment, vascularization, and tumor microenvironment, among others. All of these can contribute to the disconnects often observed in the translation of fundamental research studies into the clinic ( Roarty and Echeverria, 2021 ).…”

Anti-CTLA-4 and anti-PD-1 immunotherapies repress tumor progression in preclinical breast and colon model with independent regulatory T cells response

“…We also investigated the effect of both immunotherapies on the intravenous-based experimental metastasis model [37] . This model allows analyzing the effect of substances on extravasation and lung parenchyma colonization processes [38] . Immunotherapies were tested in both 4T1 and CT26 metastasis models.…”

Current methods for studying metastatic potential of tumor cells

“…However, the most commonly used organism to study the mechanisms of tumor formation, tumor growth and metastatic cascade processes in vivo is the domestic mouse (Mus musculus) [131][132][133]. The study of carcinogenesis in mice enables having a tumor, circulating tumor cells and metastasis in one animal at the same time [134]. Different immune system variants of mice have been established for in vivo research (Fig.…”

“…In vivo, mainly PDX models made of tumors or patientderived organoids with humanized components of the tumor microenvironment, especially with a more physiologically relevant immune system, are state-of-the-art techniques whose results may be better transferable to the clinic [134,143]. There is an increasing trend of combining mice models in one analysis to overcome bias caused by murine types [185].…”