Milk Duct Engraftment Allows Preclinical Modeling of ER⁺ Breast Cancer

Appropriate in vivo models are lacking for estrogen receptor α–positive (ER⁺) breast cancers, which constitute the majority of breast cancers. Available ER⁺ cell line xenograft models are generated by mammary fat pad injection, and resulting tumors require exogenous estradiol at higher serum levels than occur in most patients. Further, patient-derived xenografts (PDX) have also been difficult to establish. A mouse intraductal (MIND) model, where tumor cells are injected into the mouse milk duct system, had previously been used to recapitulate ductal carcinoma in situ. Sflomos and colleagues hypothesized that the milk duct would provide a suitable microenvironment to study breast cancer in the presence of physiologic levels of hormones, and observed that MIND xenografts of ER⁺ breast cancer cell lines achieved a high engraftment rate without hormone supplements and recapitulated the histopathology and kinetics of human ER⁺ tumors. Like their human counterparts, ER⁺ MIND xenografts most commonly metastasized to the bones, lungs, and brain, whereas fat pad xenografts exhibited few brain and no bone metastases. Principal component analysis of gene expression data showed that MIND xenografts clustered with luminal B breast tumor samples, whereas fat pad xenografts fell outside of the tumor subtype clusters, further indicating that the ER⁺ MIND xenografts may more faithfully recapitulate human disease. ER⁺ MIND xenografts had increased expression of Hippo pathway genes, which may explain their higher propensity to metastasize, whereas fat pad xenografts had increased TGFβ signaling, resulting in enhanced SLUG expression, which abrogated the luminal features required for growth. The ER⁺ MIND xenografts were genomically stable and retransplantable, suggesting their utility in personalized therapy, and allowed for the generation of PDXs with high efficiency. Altogether, this study demonstrates that ER⁺ MIND xenografts recapitulate the human disease, and as they respond to drugs like their clinical counterparts, they may be utilized in translational research and personalized breast cancer therapy.

Sflomos G, Dormoy V, Metsalu T, Jeitziner R, Battista L, Scabia V, et al. A preclinical model for ERα-positive breast cancer points to the epithelial microenvironment as determinant of luminal phenotype and hormone response. Cancer Cell 2016;29:407–22.