American Association for Cancer Research
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Figure S5 from Neutrophil Elastase Remodels Mammary Tumors to Facilitate Lung Metastasis

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journal contribution
posted on 2024-04-02, 07:22 authored by Amriti R. Lulla, Said Akli, Cansu Karakas, Joseph A. Caruso, Lucas D. Warma, Natalie W. Fowlkes, Xiayu Rao, Jing Wang, Kelly K. Hunt, Stephanie S. Watowich, Khandan Keyomarsi

Supplementary Figure S5: Reverse Phase Protein Array (RPPA) analysis was conducted on TAN negative and TAN positive patient samples described in Figure 1, using 174 validated antibodies. The mean of the normalized, linear RPPA values are reported for each group. (A) Relative abundance of pp90RSK T359/S363 and pRb S807 in TAN negative and TAN positive patient samples. (B) The table summarizes the top 20 antibodies that were statistically altered between the TAN negative and TAN positive groups. Statistical comparisons of TAN-positive and TAN-negative cohorts were performed using the Mann-Whitney U-test.


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Cancer Prevention and Research Institute of Texas (CPRIT)



Metastatic disease remains the leading cause of death due to cancer, yet the mechanism(s) of metastasis and its timely detection remain to be elucidated. Neutrophil elastase (NE), a serine protease secreted by neutrophils, is a crucial mediator of chronic inflammation and tumor progression. In this study, we used the PyMT model (NE+/+ and NE−/−) of breast cancer to interrogate the tumor-intrinsic and -extrinsic mechanisms by which NE can promote metastasis. Our results showed that genetic ablation of NE significantly reduced lung metastasis and improved metastasis-free survival. RNA-sequencing analysis of primary tumors indicated differential regulation of tumor-intrinsic actin cytoskeleton signaling pathways by NE. These NE-regulated pathways are critical for cell-to-cell contact and motility and consistent with the delay in metastasis in NE−/− mice. To evaluate whether pharmacologic inhibition of NE inhibited pulmonary metastasis and phenotypically mimicked PyMT NE−/− mice, we utilized AZD9668, a clinically available and specific NE inhibitor. We found AZD9668 treated PyMT-NE+/+ mice showed significantly reduced lung metastases, improved recurrence-free, metastasis-free and overall survival, and their tumors showed similar molecular alterations as those observed in PyMT-NE−/− tumors. Finally, we identified a NE-specific signature that predicts recurrence and metastasis in patients with breast cancer. Collectively, our studies suggest that genetic ablation and pharmacologic inhibition of NE reduces metastasis and extends survival of mouse models of breast cancer, providing rationale to examine NE inhibitors as a treatment strategy for the clinical management of patients with metastatic breast cancer.