Abstract
Matrix metalloproteinase 11 (MMP11) is an extracellular proteolytic enzyme belonging to the matrix metalloproteinase (MMP11) family. These proteases are involved in extracellular matrix (ECM) remodeling and activation of latent factors. MMP11 is a negative regulator of adipose tissue development and controls energy metabolism in vivo. In cancer, MMP11 expression is associated with poorer survival, and preclinical studies in mice showed that MMP11 accelerates tumor growth. How the metabolic role of MMP11 contributes to cancer development is poorly understood. To address this issue, we developed a series of preclinical mouse mammary gland tumor models by genetic engineering. Tumor growth was studied in mice either deficient (Loss of Function-LOF) or overexpressing MMP11 (Gain of Function-GOF) crossed with a transgenic model of breast cancer induced by the polyoma middle T antigen (PyMT) driven by the murine mammary tumor virus promoter (MMTV) (MMTV-PyMT). Both GOF and LOF models support roles for MMP11, favoring early tumor growth by increasing proliferation and reducing apoptosis. Of interest, MMP11 promotes Insulin-like Growth Factor-1 (IGF1)/protein kinase B (AKT)/Forkhead box protein O1 (FoxO1) signaling and is associated with a metabolic switch in the tumor, activation of the endoplasmic reticulum stress response, and an alteration in the mitochondrial unfolded protein response with decreased proteasome activity. In addition, high resonance magic angle spinning (HRMAS) metabolomics analysis of tumors from both models established a metabolic signature that favors tumorigenesis when MMP11 is overexpressed. These data support the idea that MMP11 contributes to an adaptive metabolic response, named metabolic flexibility, promoting cancer growth.
Highlights
IntroductionIn addition to cancer cells, the tumor microenvironment (TME) plays an important role in breast cancer progression [2]
Breast cancer is a leading cause of death by cancer in women [1]
In the MMP11Tg model, Matrix metalloproteinase-11 (MMP11) is expressed under the control of the keratin 14 promoter (Figure S1), this construct leads to the presence of the MMP11 protein in the skin, a highly vascularized tissue (Figures S1, S2A, and S2B), and results in a complete body exposure to MMP11 [12]
Summary
In addition to cancer cells, the tumor microenvironment (TME) plays an important role in breast cancer progression [2]. Adipocytes are an emerging cellular component of the TME, they have a direct impact on cancer cells by cell-cell contacts, and an indirect contribution by a paracrine action [3]. Matrix metalloproteinase-11 (MMP11), called stromelysin-3, is a protein secreted by stromal cells during breast cancer invasion, and increased MMP11 levels have been associated with poor outcome in cancer patients [4,5,6,7]. In the context of breast cancer, MMP11 is a TME component expressed by cancer-associated fibroblasts (CAFs) in the tumor center and by cancer-associated adipocytes (CAAs) at the tumor invasive front [3,7,8].
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