Chordin-Like 1 Suppresses Bone Morphogenetic Protein 4-Induced Breast Cancer Cell Migration and Invasion

Abstract

ShcA is an important mediator of ErbB2-and transforming growth factor ␤ (TGF-␤)-induced breast cancer cell migration, invasion, and metastasis. We show that in the context of reduced ShcA levels, the bone morphogenetic protein (BMP) antagonist chordin-like 1 (Chrdl1) is upregulated in numerous breast cancer cells following TGF-␤ stimulation. BMPs have emerged as important modulators of breast cancer aggressiveness, and we have investigated the ability of Chrdl1 to block BMP-induced increases in breast cancer cell migration and invasion. Breast cancer-derived conditioned medium containing elevated concentrations of endogenous Chrdl1, as well as medium containing recombinant Chrdl1, suppresses BMP4-induced signaling in multiple breast cancer cell lines. Live-cell migration assays reveal that BMP4 induces breast cancer migration, which is effectively blocked by Chrdl1. We demonstrate that BMP4 also stimulated breast cancer cell invasion and matrix degradation, in part, through enhanced metalloproteinase 2 (MMP2) and MMP9 activity that is antagonized by Chrdl1. Finally, high Chrdl1 expression was associated with better clinical outcomes in patients with breast cancer. Together, our data reveal that Chrdl1 acts as a negative regulator of malignant breast cancer phenotypes through inhibition of BMP signaling. Breast cancer is a heterogeneous disease that can be subdivided into distinct molecular subtypes through the integration of gene expression and genomics data (1, 2). While ErbB2 ϩ breast cancers are considered a poor-prognosis subtype (3), other signaling pathways can further modulate their malignant phenotypes. The transforming growth factor ␤ (TGF-␤) family is a prominent example that has been shown to enhance the migratory, invasive, and metastatic abilities of ErbB2 ϩ breast cancer cells (4-7). We have previously demonstrated that the ShcA adaptor protein plays an important role, downstream of TGF-␤ and ErbB2 signaling pathways, in mediating these cellular responses (8, 9). Loss of ShcA expression in ErbB2-expressing cells significantly reduced tumor growth, which was the result of reduced proliferation, diminished endothelial cell recruitment, and elevated apoptosis (9). In the present study, through the use of microarray based transcriptional profiling, we identified elevated levels of chordin-like 1 (Chrdl1) in ErbB2 ϩ breast cancer cells following TGF-␤ stimulation; however, this upregulation of Chrdl1 occurs only in the context of diminished ShcA levels.Bone morphogenetic proteins (BMPs) are secreted cytokines that belong to the TGF-␤ family of proteins, and their aberrant expression is observed in numerous cancers, including breast cancer (10). However, much like the TGF-␤ isoforms, there are conflicting reports on whether BMPs exert pro-or antitumorigenic effects on cancer cells (11,12). In breast cancer, BMP4 has been shown to promote cancer cell migration and invasion (13-16). Similarly, BMP7 induces breast cancer cell proliferation, migration/invasion, and metastasis (17, 18). Interestingly, BMP4 an...

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