In Vitro Human INtraDuctal (HIND) Model of Early Stage Breast Cancer Progression Heterogeneity

About This Grant

ABSTRACT: In Vitro Human INtraDuctal (HIND) Model of Early Stage Breast Cancer Progression Heterogeneity This project will improve the physiological relevance and handling efficiency of breast cancer cells for early-stage breast cancer progression research. This project learns from progression behavior observed in the Mouse INtraDuctal (MIND) model where human breast cancer cells are injected directly into the mammary ducts of immunocompromised mice. The goal of this project is to reproduce the “replacement” and “expansive” growth behavior of breast cancer cells observed in the MIND model −arguably the most advanced early-stage breast cancer model today− but using all human cells and in a high-throughput 384 well format. This model will use inverted mammary organoids to recreate the normal epithelium, cell-produced basement membrane, epithelial stretch, and stroma present in the MIND model but in an inverted geometry to avoid need for injection of cancer cells. This is referred to as the inverted Human INtraDuctal (iHIND) model. Advanced iHIND variants that incorporate aromatase-active epithelium and adipocytes (mouse mammary epithelium and adipocytes do not express aromatase) and hence improve upon a limitation of the MIND model, will also be bioengineered. While the iHIND model will be applicable for study of all types of breast cancer cells, a particular goal is to recapitulate the behaviors of estrogen receptor positive (ER+) breast cancer cells and their environments as they dynamically interact with the normal epithelium and stroma to progress from in situ to invasive stages. ER+ breast cancers are clinically the most prevalent, yet there are few in vitro or in vivo models, other than the MIND model, that recapitulate early-stage progression. The aims of this project are: Aim 1. Validate Disease Progression Heterogeneity Arising from Breast Cancer Cell Type Diversity. This aim will benchmark the iHIND model to the MIND model using well-characterized breast cancer cell lines. Aim 2. Bioengineer Disease Progression Heterogeneity Arising from the Duct Microenvironment (DME) Diversity. This aim will analyze disease progression in iHIND models that represent types of DMEs that are physiologically relevant but difficult to realize using murine mammary ducts. Aim 3. Disseminate and Expand Use of the iHIND Model. This aim will develop protocols to culture patient- derived breast cancer organoid cells and fresh patient-derived breast cancer cells. Although not all in situ breast cancers become invasive, currently an overwhelming majority are treated. This project will help alleviate over-diagnosis and over-treatment of early-stage breast cancer by providing better tissue models and biospecimen handling methods that recapitulate early-stage breast cancer progression.