S100A10 Has a Critical Regulatory Function in Mammary Tumor Growth and Metastasis: Insights Using MMTV-PyMT Oncomice and Clinical Patient Sample Analysis

Simple Summary The key challenges that face patients during breast cancer therapy is the metastatic spread and aggressiveness of the disease. Thus, the goal of current breast cancer research is to discover new therapeutic and diagnostic targets that limit the aggressive spread of the cancer. In this study, we investigated the role of protein S100A10 (p11) in breast tumor growth, progression, and metastasis using mouse cancer models and patient tumor sample analysis. We have demonstrated in our previous studies that p11 is critical for the function of a proteolytic enzyme-plasmin, which aids in the digestion of the tissues surrounding the tumor and allows the escape of the cancer cells from the breast tissue to organs such as the lungs and bone. Here, we present evidence that genetic deletion of p11 results in smaller and less aggressive mammary tumors in mice. We also observed that the cancer spread to the lungs is dramatically reduced in the absence of p11 gene in mice. Subsequent analysis of breast cancer patient tissues showed a correlation between higher p11 expression and both poor survival and aggressive cancer. S100A10 (p11) is a plasminogen receptor that regulates cellular plasmin generation by cancer cells. In the current study, we used the MMTV-PyMT mouse breast cancer model, patient tumor microarray, and immunohistochemical (IHC) analysis to investigate the role of p11 in oncogenesis. The genetic deletion of p11 resulted in significantly decreased tumor onset, growth rate, and spontaneous pulmonary metastatic burden in the PyMT/p11-KO (knock-out) mice. This phenotype was accompanied by substantial reduction in Ki67 positivity, macrophage infiltration, decreased vascular density in the primary tumors, and decrease in invasive carcinoma and pulmonary metastasis. Surprisingly, IHC analysis of wild-type MMTV-PyMT mice failed to detect p11 expression in the tumors or metastatic tumor cells and loss of p11 did not decrease plasmin generation in the PyMT tumors and cells. Furthermore, tumor cells expressing p11 displayed dramatically reduced lung metastasis when injected into p11-depleted mice, further strengthening the stromal role of p11 in tumor growth and metastasis. Transcriptome analysis of the PyMT tumors from p11-KO mice showed marked reduction in genes such as Areg, Muc1, and S100a8 involved in breast cancer development, progression, and inflammation. The PyMT/p11-KO tumors displayed a remarkable increase in inflammatory cytokines such as interleukin (Il)-6, Il-10, and interferon (Ifn)-gamma. Gene expression profiling and IHC of primary breast cancer samples showed that p11 mRNA and protein levels were significantly higher in tumor tissues compared to normal mammary tissue. P11 mRNA expression was significantly associated with poor patient prognosis and significantly elevated in high grade, triple negative (TN) tumors, and tumors with high proliferative index. This is the first study examining the crucial role of p11 in breast tumor development and metastasis, thus emphasizing its potential as a diagnostic and prognostic biomarker in breast cancer.