Abstract 2747: Loss of S100A10 gene suppresses mammary tumor progression in PyMT mouse tumor model
Authors: Bharadwaj Alamelu , Holloway Ryan , Colp Patricia , Liu Rong-Zong , Godbout Rosaline , Barnes Penny , Marignani Paola A. , Waisman David 
Published: August 2019

Introduction: S100A10 (p11) is a plasminogen receptor that we have shown is a master regulator of cellular plasmin generation by cancer cells and is also is essential and sufficient for macrophage migration to tumor sites. In the current study we have investigated the role of p11 in breast cancer tumor progression.

Methods: We have employed gene profiling analysis of breast cancer patient tumors and an in depth study of the Polyoma Middle T (PyMT) transgenic mouse breast cancer model to interrogate the possible role of p11 in breast cancer.

Results: Gene expression profiling from 176 primary breast cancer samples obtained through the CBCF tumor bank showed that p11 mRNA levels were significantly higher in tumors with high Ki67 immunoreactivity, was upregulated in high grade breast tumors, and was also significantly associated with poor patient prognosis (hazard ratio of 3.34). To further investigate the function of p11 in breast cancer, we established the MMTV-PyMT transgenic mouse mammary breast cancer model and generated two groups of animals – PyMT/p11-WT and PyMT/p11-null mice. We observed a significant delay in tumor onset and appearance of palpable tumours ias well as a dramatic reduction (5-fold at 20 weeks) in tumor growth in mice lacking p11 compared to WT controls. Importantly, the total tumor burden at the time of sacrifice was 3.5-fold lower for the p11-null mice concomitant with decreased tumour cell proliferation (Ki67), vascularity (CD31) and macrophage infiltration (F4/80). The histopathological progression to late carcinoma was delayed in PyMT/p11-null mice, with only 6% of PyMT/p11-null mice showing late carcinoma as compared to 69% PyMT/p11-WT at 20 weeks. Consistently, there was a 5-fold decrease in total metastatic foci in the lungs of the PyMT/p11-null mice. Experimental metastasis assay of p11-WT cells injected in p11-WT and p11-null mice showed a dramatic decrease in metastatic burden in p11-null mice suggesting a stromal involvement. Interestingly loss of p11 did not decrease plasmin generation in the PyMT tumors and cells obtained from tumors. Surprisingly, we also observed decreased plasmin independent migration and invasion with loss of p11.

Conclusions: These studies suggest that p11 plays a critical role in breast tumor growth and metastasis, independent of its role as a plasminogen receptor. Future studies are aimed at elucidating the tumor cell or stroma specific role of p11 in breast cancer progression and identifying the intracellular function of p11 in this process.

Citation Format: Alamelu Bharadwaj, Ryan Holloway, Patricia Colp, Rong-Zong Liu, Rosaline Godbout, Penny Barnes, Paola A. Marignani, David Waisman. Loss of S100A10 gene suppresses mammary tumor progression in PyMT mouse tumor model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2747.