Expression of MMP-11, an estrogen-suppressed gene in MCF-7 cells, is elevated upon acquisition of tamoxifen resistance

Abstract

Matrix metalloproteinase-11 (MMP-11), also known as stromelysin-3, is a member of a large family of zinc-dependent proteinases. Known to be expressed in breast tumor stroma, the epithelium, and the associated mononuclear inflammatory cells, its expression is associated with invasion, metastasis, and poor clinical outcomes and survival rates. Despite the known effects of estrogen on extracellular matrix remodeling, and breast cancer metastasis, the role of MMP-11 therein is not understood. Here, we show that estrogen suppresses MMP-11 expression in MCF-7 breast cancer cells via a mechanism that involves binding of the estrogen receptor α (ERα) to an estrogen response element located in the intron-1 of MMP-11. ERα knockdown alone upregulates MMP-11 expression, highlighting its crucial role in this regulatory axis. Additionally, the anti-estrogen tamoxifen (4-OHT) blocks estrogen-mediated MMP-11 suppression. However, prolonged 4-OHT exposure or 4-OHT resistance leads to increased MMP-11 expression. This suggests that MMP-11 may play a role in 4-OHT resistance, potentially leading to a more aggressive tumor phenotype. Our study underscores the importance of estrogen-ERα signaling in breast cancer progression, emphasizing the need for further investigation into MMP-11's role in 4-OHT resistance and cancer metastasis.