Defining the Dormant Tumor Microenvironment for Breast Cancer Prevention and Treatment

摘要

Tamoxifen and parity induce ECM remodeling resulting in microenvironments that are anticipated to be inhibitory to breast cancer progression. Given the technical difficulties in studying tumor cell dormancy in the context of secondary lesions, we propose to use suppression at the primary site as a model for breast cancer dormancy. Aims: 1) Identify ECM proteins of the quiescent mammary gland. 2) Determine whether a reconstituted tumor suppressive ECM causes tumor cells to enter a quiescent/dormant-like state in vitro. 3) Validate the tumor suppressive rat ECM signature in breast tissue of parous women and in women with anti-estrogen treatment compared to controls using IHC assays. Results: Mammary ECM isolated from parous rats suppressed tumor progression in in vitro and in vivo assays, and supported adherens junction formation. Mass spec-based proteomics and label-free quantitative analysis identified an increase in collagen I in parous compared to nulliparous rat mammary glands; data that contradicts the paradigm that higher fibrillar collagen density is tumor promotional. Analysis of collagen architecture revealed an increased amount of anisotropic collagen fibers in parous glands relative to nulliparous glands, suggesting reduced tensional properties with parity. Impact on Breast Cancer Research/ Patients: Objective: identify ECM proteins that support tumor cell dormancy for the purpose of developing cell culture conditions suitable for screening drugs targeting dormancy. This work has the potential to yield high impact data and open new avenues of investigation into mechanisms and targeting of tumor dormancy.