Role of the Tumor Microenvironment in Modulating Drug Response in ER-Positive Breast Cancer (Study from Co-Culture Systems)

Abstract

Abstract
Estrogen receptor–positive breast cancer represents the most prevalent molecular subtype of breast malignancy and remains a major clinical challenge due to the frequent development of resistance to endocrine and chemotherapeutic agents. Increasing evidence suggests that this resistance is not solely driven by intrinsic tumor cell alterations but is strongly influenced by the surrounding tumor microenvironment. In particular, cancer-associated fibroblasts play a pivotal role in regulating tumor progression, survival signalling, and therapeutic response through complex paracrine interactions, extracellular matrix remodelling, and metabolic support. This study explores the impact of heterogeneous co-culture systems comprising ER⁺ breast cancer cells and fibroblasts to better understand stromal-mediated drug resistance mechanisms. By analysing existing co-culture-based experimental datasets, the study compares drug sensitivity in conventional monoculture models with three-dimensional fibroblast–tumor co-culture models. The findings demonstrate that fibroblast-rich microenvironments significantly reduce the efficacy of endocrine therapies such as tamoxifen and fulvestrant, as well as cytotoxic drugs, by activating alternative growth factor signalling pathways, enhancing extracellular matrix deposition, and promoting pro-survival metabolic reprogramming. Overall, the study highlights the limitations of traditional monoculture drug screening platforms and emphasises the importance of tumor microenvironment-inclusive models for accurate prediction of clinical drug responses. Understanding stromal–epithelial crosstalk provides a rational foundation for developing combination therapies that simultaneously target tumor cells and their supportive microenvironment, thereby offering improved strategies for overcoming endocrine resistance in ER⁺ breast cancer.
Keywords
ER-positive breast cancer, Tumor microenvironment, Cancer-associated fibroblasts, Drug resistance, Co-culture model, Endocrine therapy