Background: Triple-negative breast cancers [ER/PR-/-, HER2/neu wt] are frequently metastatic at diagnosis and at 5-years only 14% of African American women are alive. In addition to being poorly differentiated, triple-negative breast cancers frequently have little or no associated DCIS. As a result, the precursor lesion for triple-negative breast cancer is poorly understood. Here we aim to investigate whether the aggressive biology that defines triple-negative breast cancer exists in pre-malignant breast lesions from high-risk African American women.
Epithelial plasticity (EMT and the reverse process, MET) is hypothesized to play a key role in defining the aggressive behavior of triple-negative breast cancer. The prevailing model is that epithelial triple-negative breast cancer undergoes EMT, invades into the peripheral vasculature, and then undergoes the reverse process, MET, in order to develop distal metastasis.
Stat3 is an inflammatory-kinase that predicts poor prognosis in triple-negative breast cancer, and is also regulated by ECM signaling. Stat3 is known to promote EMT, stem cell regeneration, and induces a subclass of microRNAs [miR200/Let-7/miR203/mi149] that promote EMT and invasion. Activated Stat3-pTyr705 heterodimerizes and transcriptionally regulates vimentin.
Results: We performed high-resolution proteomic-profiling and immunohistochemical staining of premalignant breast lesions from high-risk African American women that had contralateral triple-negative breast cancer; 100 cores were tested/breast. Activation of Stat3/vimentin-signaling (proteomic profiling) and expression of vimentin/nuclear Snail-1 (IHC) was first observed in the earliest identifiable lesions (columnar change and atypical hyperplasia). Combined miRNA and proteomic profiling of mammary atypia from high-risk African American women identified activation of Stat3 network signaling (IL6/Stat3/Akt/vimentin) and modulation of Stat3-regulated miRNAs.
Conclusions: We observe activation of Stat3/vimentin/miRNA-network signaling in mammary atypia from high-risk women. These observations provide evidence that the signaling pathways that promote the aggressive phenotype of triple-negative breast cancer may be activated in mammary atypia.