Intraductal Adaptation of the 4T1 Mouse Model of Breast Cancer Reveals Effects of the Epithelial Microenvironment on Tumor Progression and Metastasis

Abstract

Background: Low success rates in oncology drug development are prompting re-evaluation of preclinical models, including orthotopic tumor engraftment. In breast cancer models, tumor cells are typically injected into mouse mammary fat pads (MFP). However, this approach bypasses the epithelial microenvironment, potentially altering tumor properties in ways that affect translational application. Materials and Methods: Tumors were generated by mammary intraductal (MIND) engraftment of 4T1 carcinoma cells. Growth, histopathology, and molecular features were quantified. Results: Despite growth similar to that of 4T1 MFP tumors, 4T1 MIND tumors exhibit distinct histopathology and increased metastasis. Furthermore, >6,000 transcripts were found to be uniquely up-regulated in 4T1 MIND tumor cells, including genes that drive several cancer hallmarks, in addition to two known therapeutic targets that were not up-regulated in 4T1 MFP tumor cells. Conclusion: Engraftment into the epithelial microenvironment generates tumors that more closely recapitulate the complexity of malignancy, suggesting that intraductal adaptation of orthotopic mammary models may be an important step towards improving outcomes in preclinical drug screening and development.

The past, present, and future of breast cancer models for nanomedicine development

“…The generation of orthotopic breast cancer models via the injection of breast cancer cells inside the natural cavity of the mammary ducts (intraductal) provides for the histological and molecular features of the clinical setting, high implantation rates, and effective spontaneous metastasis [125] , [130] . Unfortunately, the intraductal strategy remains technically challenging and has yet to find common use regarding nanomedicine evaluation [135] , [136] , [137] , [138] .…”

Comparative Profiling of Metastatic 4T1- vs. Non-metastatic Py230-Based Mammary Tumors in an Intraductal Model for Triple-Negative Breast Cancer

“…Mouse models that replicate human breast cancer play an essential role in the preclinical screening of such drugs. To this end, we and others have shown that inoculation of mammary tumor cells in the murine mammary ductal environment, also referred to as the mouse intraductal (MIND) model, provides a significant advantage over the classical fat pad model as it allows to monitor disease progression from early DCIS to invasive carcinoma (IC) (3)(4)(5)(6)(7)(8)(9)(10). Recently, we at first identified the stimulatory role of macrophage polarization in ductal breakthrough and metastatic progression in triple-negative breast cancer (TNBC) using a model based on intraductal inoculation of 4T1 mammary tumor cells in syngeneic BALB/c mice, suggesting that macrophage polarization is a potential immunotherapeutic target (4).…”

When left does not seem right: epigenetic and bioelectric differences between left- and right-sided breast cancer

“…In particular, tumors in bilateral organs such as breast, colon, kidney or lung, show subtle but significant differences at morphological, genetic, molecular and incidence levels (Robichaux et al 2014 ; Yang et al 2018 ). Research data from our group and others (of diverse disciplines such as embryogenesis, development, molecular oncology, or cellular biology), have proposed that the asymmetric tumor microenvironment of bilateral organs could be part of the explanation for the L/R differences in cancer (Levin et al 2016 ; Ma 2013 ; Robichaux et al 2014 ; Campoy et al 2016 ; Atiya et al 2019 ; Yi et al 2021 ).…”