Abstract
Metastasis is the deadliest and most poorly understood feature of malignant diseases. Recent work has shown that Metadherin (MTDH) is overexpressed in over 40% of breast cancer patients and promotes metastasis and chemoresistance in experimental models of breast cancer progression. Here we applied mass spectrometry-based screen to identify staphylococcal nuclease domain-containing 1 (SND1) as a candidate MTDH-interacting protein. After confirming the interaction between SND1 and MTDH, we tested the role of SND1 in breast cancer and found that it strongly promotes lung metastasis. SND1 was further shown to promote resistance to apoptosis and to regulate the expression of genes associated with metastasis and chemoresistance. Analyses of breast cancer clinical microarray data indicated that high expression of SND1 in primary tumors is strongly associated with reduced metastasis-free survival in multiple large scale data sets. Thus, we have uncovered SND1 as a novel MTDH-interacting protein and shown that it is a functionally and clinically significant mediator of metastasis.
Highlights
Investigations of how MTDH promotes such powerful phenotypes have generally focused on MTDH signaling in the context of classical oncogenic pathways, such as Ha-Ras [15], PI3K/AKT [13], ERK, and Wnt/-catenin [8], and NF-B [49]
The MTDHBCCIP␣ interaction was mapped to MTDH amino acids 72–169, whereas PLZF was shown to interact with two regions of MTDH, amino acids 1–285 and 487–582
We have mapped the region of interaction to amino acids 364 – 470 of the MTDH coding sequence, which is very similar to the proposed MTDH lung-homing domain, highlighting this region as crucial for MTDH interactions and functionality
Summary
Recipient of a United States Department of Defense predoctoral fellowship. Investigator of the Champalimaud Metastasis Program at Princeton University. Prior work on MTDH molecular mechanisms has largely focused on hypothesis-driven investigations into the ability of MTDH to influence classical oncogenic pathways with little exploration to date on protein-level interactions [16, 21]. We aimed to expand the knowledge of MTDH molecular functionality and uncover novel genes involved in promoting distant metastasis. We report experimental and clinical data indicating that, in addition to interacting with MTDH, SND1 is in its own right a powerful novel mediator of breast cancer lung metastasis
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