Meta-Analysis: 7,12-Dimethylbenz[a]anthracene (DMBA) Induces Diverse Types of Breast Carcinoma in Rat Models: A Systematic Review of Tumor Histopathology and Pathogenesis

Aim: 7,12-Dimethylbenz[a]anthracene (DMBA) is a potent polycyclic aromatic hydrocarbon (PAH) widely used to induce mammary carcinogenesis in rodent models. This meta-analysis systematically reviews and synthesizes the evidence on the histopathological diversity of DMBA-induced breast tumors in rats and the molecular mechanisms underpinning this carcinogenesis.
Materials and Methods: A systematic search of PubMed, Embase, Web of Science, and Scopus was conducted for studies published from inception to March 2024. Studies administering DMBA to female rat models and reporting detailed histopathological classification of resultant mammary tumors were included. Data on tumor incidence, latency, and type (adenocarcinoma, fibroadenoma, etc.) were extracted. Pooled incidence rates with 95% confidence intervals (CI) were calculated using a random-effects model. Molecular data on DMBA metabolism, DNA adduct formation, and oncogenic pathways were synthesized qualitatively.
Results: 48 studies (n= 2,815 rats) were included. The pooled incidence of malignant mammary tumors (primarily adenocarcinomas) was 76.4% (95% CI: 70.1–82.7%, I² = 87%). The pooled incidence of benign tumors (primarily fibroadenomas) was 58.2% (95% CI: 49.5–66.9%, I² = 89%). A significant proportion of animals developed multiple tumor types. Histopathological analysis revealed a spectrum of lesions, including invasive ductal carcinomas, papillary carcinomas, cribriform carcinomas, and squamous cell carcinomas. Tumor development was highly dependent on the timing of DMBA administration relative to the animal's estrous cycle and age. The carcinogenic mechanism is initiated by cytochrome P450 (CYP1B1)-mediated metabolic activation to DMBA-3,4-dihydrodiol-1,2-epoxide, which forms stable DNA adducts, primarily with adenine residues, leading to consistent H-ras oncogene activation via a specific A→T transversion at the second nucleotide of codon 61.
Conclusion: DMBA induction in rats produces a heterogeneous and reproducible profile of mammary tumors that closely mimics the heterogeneity of human breast cancer. The high incidence and predictable molecular pathogenesis, centered on ras activation, make the DMBA model an invaluable tool for studying breast cancer chemoprevention, tumor progression, and the efficacy of therapeutic interventions.