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

Abstract

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)-γ. 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.

The ANXA2/S100A10 Complex—Regulation of the Oncogenic Plasminogen Receptor

“…We proposed that S100A10-dependent plasmin generation plays a critical role in the movement of macrophages to the tumor site and, therefore, S100A10 was essential and sufficient for macrophage migration to tumor sites. Next, we established the MMTV-PyMT (mouse mammary tumor virus-polyoma middle tumor-antigen) transgenic breast cancer model in wild-type and S100A10 knockout mice and used this double transgenic model to investigate the role of S100A10 in breast cancer malignancy [ 188 ]. The MMTV-PyMT model is a significant advance in the study of oncogenesis because it recapitulates all the phases of oncogenesis.…”

Clinical significance of serum S100A10 in lung cancer

“… 20 In a study of breast cancer, S100A10 expression was significantly elevated in high-grade, triple-negative tumours and tumours with a high proliferative index. 8 In a study of lung squamous cell carcinoma tissue, S100A10 levels were significantly associated with higher TNM stage, tumour size, lymphatic invasion and lymph node metastasis. 11 The results of these studies were consistent with literature reporting that serum S100A10 is related to cancer characteristics.…”

“… 5 Previous reports have indicated that S100A10 acts as an oncoprotein in ovarian cancer, gastric cancer, breast cancer and renal cell cancer. 6 – 9 In lung cancer, S100A10 is likely involved in the progression of invasion and metastasis through regulation of plasmin production and subsequent plasmin-dependent stimulation of matrix metalloproteinase (MMP)-2 and MMP-9. 10 A previous report demonstrated that S100A10 tissue levels were higher in cancer tissues.…”

Plasminogen Receptors and Fibrinolysis

“…The phenotypes of plasminogen and Plg-R KT −/− mammary glands are also distinct, in that plasminogen deficiency results in delays in ductal development during puberty [ 82 ] that are not observed in Plg-R KT −/− glands [ 83 ]. Recently, the loss of S100A10 has been shown to impair ductal development during the early stages of mammary development [ 84 ]. Thus, mammary development provides an example of the utilization of multiple plasminogen receptors at distinct steps in a physiologic process.…”