DMBA promotes ErbB2-mediated carcinogenesis via ErbB2 and estrogen receptor pathway activation and genomic instability

Environmental factors, including 7,12-dimethylbenz [a]anthracene (DMBA) exposure, and genetic predisposition, including ErbB2 overexpression/amplification, have been demonstrated to increase breast cancer susceptibility. Although DMBA- and ErbB2-mediated breast cancers are well-studied in their respective models, key interactions between environmental and genetic factors on breast cancer risk remain unclear. Therefore, the present study aimed to investigate the effect of DMBA exposure on ErbB2-mediated mammary tumorigenesis. MMTV-ErbB2 transgenic mice exposed to DMBA (1 mg) via weekly oral gavage for 6 weeks exhibited significantly enhanced mammary tumor development, as indicated by reduced tumor latency and increased tumor multiplicity compared with control mice. Whole mount analysis of premalignant mammary tissues from 15-week-old mice revealed increased ductal elongation and proliferative index in DMBA-exposed mice. Molecular analyses of premalignant mammary tissues further indicated that DMBA exposure enhanced epidermal growth factor receptor (EGFR)/ErbB2 and estrogen receptor (ER) signaling, which was associated with increased mRNA levels of EGFR/ErbB2 family members and ER-targeted genes. Furthermore, analysis of tumor karyotypes revealed that DMBA-exposed tumors displayed more chromosomal alterations compared with control tumors, implicating DMBA-induced chromosomal instability in tumor promotion in this model. Together, the data suggested that DMBA-induced deregulation of EGFR/ErbB2-ER pathways plays a critical role in the enhanced chromosomal instability and promotion of ErbB2-mediated mammary tumorigenesis. The study highlighted gene-environment interactions that may increase risk of breast cancer, which is a critical clinical issue.