DCIS Progression and the Tumor Microenvironment: Molecular Insights and Prognostic Challenges

Abstract

Ductal carcinoma in situ (DCIS) is the most common form of non-invasive breast cancer and a recognized precursor to invasive ductal carcinoma (IDC). Although DCIS itself is confined to the milk duct and not immediately life-threatening, its potential for progression to invasive disease necessitates careful clinical management. The increased detection of DCIS due to advancements in imaging and widespread screening programs has raised critical questions regarding its classification, prognosis, and optimal treatment strategies. While most cases exhibit indolent behavior, others harbor molecular characteristics that drive malignant transformation. A key challenge lies in distinguishing low-risk DCIS, which may never progress, from aggressive cases requiring intervention. Tumor microenvironment dynamics, immune cell infiltration, and molecular alterations, including hormone receptor (HR) status, human epidermal growth factor 2 (HER2) expression, and genetic mutations, play crucial roles in determining disease trajectory. This review explores the biological and molecular mechanisms underlying DCIS progression, with an emphasis on myoepithelial cells, tumor-infiltrating lymphocytes, and microenvironmental factors. By integrating recent findings, this article aims to refine risk stratification approaches and guide future strategies for personalized DCIS management. Improved prognostic biomarkers and targeted therapeutic interventions could help optimize treatment decisions, balancing the need for effective cancer prevention while minimizing overtreatment in low-risk patients.

Keywords: DCIS progression; ductal carcinoma in situ; tumor microenvironment.

Figure 1

DCIS progression. Progressive stages of breast tissue transformation: starting with normal ductal epithelium, followed by ductal carcinoma in situ (DCIS) characterized by abnormal epithelial proliferation confined within the duct, then DCIS with microinvasion showing early cancer cell escape into the surrounding stroma, and finally, invasive ductal carcinoma (IDC), where malignant cells have fully breached the basement membrane and infiltrated the adjacent tissue.

Figure 2

DCIS microenvironment. Surrounding the duct, the stroma reveals a rich mosaic of non-neoplastic cell types contributing to the tumor microenvironment. Immune cells, such as macrophages and lymphocytes (including T and B cells), are dispersed throughout the stroma, indicating active immunological surveillance and potential immunoediting. Fibroblasts, including cancer-associated fibroblasts (CAFs), are embedded within the extracellular matrix among mesenchymal cells. Collagen fibers are prominently visible in the stroma, forming a dense and structured extracellular matrix that provides mechanical support and modulates cell behavior within the DCIS microenvironment. The cellular heterogeneity evident in this microenvironment underscores the dynamic crosstalk between tumor cells and stromal components.

Figure 3

Tumor progression and molecular changes. Dynamic changes in key components of the tumor microenvironment—myoepithelial cells, tumor-infiltrating lymphocytes (TILs), macrophages, fibroblasts, and collagen fibers—from normal ductal epithelium through DCIS and microinvasion to invasive ductal carcinoma are varied and numerous. Myoepithelial Cells: In normal ducts, they form a continuous layer with tumor-suppressive functions. During DCIS, they persist but lose functional integrity. With microinvasion, gaps emerge, and in IDC, they are lost at invasive sites, marking the breakdown of a critical barrier. TILs: Rare in normal tissue, they accumulate in DCIS as an immune response to dysplasia. Over time, they become dysfunctional or exhausted, particularly in invasive stages, despite increased numbers. Macrophages: Initially sparse, they are recruited during DCIS and shift to a tumor-promoting (TAM) phenotype. In IDC, they localize to invasive fronts, secreting factors that support invasion, immune evasion, and angiogenesis. Fibroblasts/CAFs: Normally maintaining ECM balance, fibroblasts activate in DCIS and differentiate into CAFs. These cells promote tumor growth and matrix remodeling, becoming increasingly abundant and interactive with other stromal cells in IDC. Collagen Fibers: Sparse and disorganized in healthy tissue, collagen becomes denser and aligned during progression. In IDC, it forms stiff, linear tracks that facilitate invasion and contribute to therapeutic resistance.