Abstract

Breast, lung, and pancreatic cancers collectively represent one third of all diagnosed tumors and are responsible for almost 40% of overall cancer mortality. Despite improvements in current treatments, efforts to develop more specific therapeutic options are warranted. Here we identify matrix metalloproteinase 3 (MMP3) as a potential target within all three of these tumor types. MMP3 has previously been shown to induce expression of Rac1b, a tumorigenic splice isoform of Rac1. In this study we find that MMP3 and Rac1b proteins are both strongly expressed by the tumor cells of all three tumor types and that expression of MMP3 protein is prognostic of poor survival in pancreatic cancer patients. We also find that MMP3 gene expression can serve as a prognostic marker for patient survival in breast and lung cancer. These results suggest an oncogenic MMP3-Rac1b signaling axis as a driver of tumor progression in three common poor prognosis tumor types, further suggesting that new therapies to target these pathways could have substantial therapeutic benefit.

Highlights

  • Lung cancer is the leading cause of death for both sexes with a 221,000 new cases and 158,000 deaths estimated for 2015 in the US [1]

  • Pancreatic adenocarcinoma tissue microarrays (TMAs) were stained for matrix metalloproteinase 3 (MMP3), Rac1b, collagen I, and H&E

  • Using collagen-1 as a marker of stromal tissue, we observed that MMP3 and Rac1b were primarily expressed in the pancreatic tumor cells (Figure 1A)

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Summary

Introduction

Lung cancer is the leading cause of death for both sexes with a 221,000 new cases and 158,000 deaths estimated for 2015 in the US [1]. Pancreatic cancer, though rarer in incidence, with estimated 49,000 new cases in 2015, ranks fourth overall in cancer related deaths for both sexes, with an estimated 40,500 deaths in 2015. Investigations of the processes involved in cancer development and tumor metastasis have identified matrix metalloproteinases (MMPs) as key factors involved in the development of the tumor microenvironment and as drivers of cancer progression and metastasis [810]. These findings generated significant enthusiasm for MMPs as therapeutic targets, but clinical trials that employed broad spectrum, small molecule catalytic site inhibitors produced disappointing results [11]. While the pharmaceutical industry has been hesitant to further explore MMP inhibitors as anticancer therapeutics following these trials, ongoing basic research suggests that more selective MMP inhibitors with lower toxicity could be achievable, and would likely produce better results, if www.impactjournals.com/Genes&Cancer targeted toward specific MMPs that are upregulated in human cancers and that drive malignant progression [15]

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