Endocrine therapy remains the cornerstone of treatment for estrogen receptor–positive (ER-positive) breast cancer; however, therapeutic resistance continues to limit long-term clinical success. While earlier studies primarily focused on tumor-intrinsic genetic alterations, emerging evidence highlights the tumor microenvironment as a decisive regulator of drug response. Among stromal components, cancer-associated fibroblasts (CAFs) have gained prominence as key drivers of tumor progression and endocrine resistance. This qualitative secondary review synthesizes peer-reviewed literature published between 2010 and 2025 to elucidate the mechanistic role of fibroblast–cancer cell interactions in shaping therapeutic outcomes. Data were systematically analyzed to identify recurring biological themes, including paracrine survival signaling, extracellular matrix remodeling, metabolic reprogramming, and induction of estrogen-independent growth pathways. Findings reveal that CAFs promote resistance through activation of PI3K/AKT and MAPK signaling, enhancement of cancer stem–like phenotypes, metabolic coupling via lactate exchange, and biomechanical alterations of the extracellular matrix that restrict drug penetration. Heterogeneous co-culture models further demonstrate that these stromal-mediated processes operate synergistically to confer tumor plasticity and sustained survival under endocrine stress. Collectively, this review underscores fibroblasts as central orchestrators of resistance in ER-positive breast cancer and emphasizes the necessity of incorporating tumor microenvironment dynamics into pharmaceutical research. The integration of stromal-targeted therapies with conventional endocrine agents, alongside the adoption of co-culture platforms in preclinical screening, may offer more durable therapeutic strategies.
Gangoutri Das* (Fri,) studied this question.