State of the Art Modelling of the Breast Cancer Metastatic Microenvironment: Where Are We?

Metastatic spread of tumour cells to tissues and organs around the body is the most frequent cause of death from breast cancer. This has been modelled mainly using mouse models such as syngeneic mammary cancer or human in mouse xenograft models. These have limitations for modelling human disease progression and cannot easily be used for investigation of drug resistance and novel therapy screening. To complement these approaches, advances are being made in ex vivo and 3D in vitro models, which are becoming progressively better at reliably replicating the tumour microenvironment and will in the future facilitate drug development and screening. These approaches include microfluidics, organ-on-a-chip and use of advanced biomaterials. The relevant tissues to be modelled include those that are frequent and clinically important sites of metastasis such as bone, lung, brain, liver for invasive ductal carcinomas and a distinct set of common metastatic sites for lobular breast cancer. These sites all have challenges to model due to their unique cellular compositions, structure and complexity. The models, particularly in vivo, provide key information on the intricate interactions between cancer cells and the native tissue, and will guide us in producing specific therapies that are helpful in different context of metastasis.

A novel preclinical model of the normal human breast.

Improved screening and treatment have decreased breast cancer mortality, although incidence continues to rise. Women at increased risk of breast cancer can be offered risk reducing treatments, such as tamoxifen, but this has not been shown to reduce breast cancer mortality. New, more efficacious, risk-reducing agents are needed. The identification of novel candidates for prevention is hampered by a lack of good preclinical models. Current patient derived in vitro and in vivo models cannot fully recapitulate the complexities of the human tissue, lacking human extracellular matrix, stroma, and immune cells, all of which are known to influence therapy response. Here we describe a normal breast explant model utilising a tuneable hydrogel which maintains epithelial proliferation, hormone receptor expression, and residency of T cells and macrophages over 7 days. Unlike other organotypic tissue cultures which are often limited by hyper-proliferation, loss of hormone signalling, and short treatment windows (< 48h), our model shows that tissue remains viable over 7 days with none of these early changes. This offers a powerful and unique opportunity to model the normal breast and study changes in response to various risk factors, such as breast density and hormone exposure. Further validation of the model, using samples from patients undergoing preventive therapies, will hopefully confirm this to be a valuable tool, allowing us to test novel agents for breast cancer risk reduction preclinically.