Complement inhibitor CSMD1 modulates epidermal growth factor receptor oncogenic signaling and sensitizes breast cancer cells to chemotherapy

Abstract

Background Human CUB and Sushi multiple domains 1 (CSMD1) is a large membrane-bound tumor suppressor in breast cancer. The current study aimed to elucidate the molecular mechanism underlying the effect of CSMD1 in highly invasive triple negative breast cancer (TNBC). Methods We examined the antitumor action of CSMD1 in three TNBC cell lines overexpressing CSMD1, MDA-MB-231, BT-20 and MDA-MB-486, in vitro using scanning electron microscopy, proteome array, qRT-PCR, immunoblotting, proximity ligation assay, ELISA, co-immunoprecipitation, immunofluorescence, tumorsphere formation assays and flow cytometric analysis. The mRNA expression pattern and clinical relevance of CSMD1 were evaluated in 3520 breast cancers from a modern population-based cohort. Results CSMD1-expressing cells had distinct morphology, with reduced deposition of extracellular matrix components. We found altered expression of several cancer-related molecules, as well as diminished expression of signaling receptors including Epidermal Growth Factor Receptor (EGFR), in CSMD1-expressing cells compared to control cells. A direct interaction of CSMD1 and EGFR was identified, with the EGF-EGFR induced signaling cascade impeded in the presence of CSMD1. Accordingly, we detected increased ubiquitination levels of EGFR upon activation in CSMD1-expressing cells, as well as increased degradation kinetics and chemosensitivity. Accordingly, CSMD1 expression rendered tumorspheres pretreated with gefitinib more sensitive to chemotherapy. In addition, higher mRNA levels of CSMD1 tend to be associated with better outcome of triple negative breast cancer patients treated with chemotherapy. Conclusions Our results indicate that CSMD1 cross-talks with the EGFR endosomal trafficking cascade in a way that renders highly invasive breast cancer cells sensitive to chemotherapy. Our study unravels one possible underlying molecular mechanism of CSMD1 tumor suppressor function and may provide novel avenues for design of better treatment.

Uncovering Oncogenic Mechanisms of Tumor Suppressor Genes in Breast Cancer Multi-Omics Data

“…Using Bonferroni’s multiple testing correction (adjusted p -value = 0.05/(508 × 7856) = 1.25 × 10 −8 ), there were 3790 significant TSG-GOBP pairs in the result of DCG analysis ( Table 2 and Supplementary Table S5 ). The most significantly enriched term in the obtained results was “mRNA processing” (GO:0006397), and the input genes were obtained from DCGs with CSMD1, which has a tumor-suppressive function [ 39 ]. The RNA processing related to GO terms, such as mRNA metabolic process (GO:0016071), RNA splicing (GO:0008380), and regulation of RNA splicing (GO:0043484), were found to be enriched significantly in several TSGs (see Supplementary Table S5 ).…”

Construction and systematic evaluation of a machine learning-based cuproptosis-related lncRNA score signature to predict the response to immunotherapy in hepatocellular carcinoma

“…Moreover, patients with mutated TP53 had worse OS and relapse-free survival times ( 45 ). CSMD1 is considered to be a tumor suppressor gene in many types of cancer, such as breast cancer ( 46 ), colorectal cancer ( 47 ), gastric cancer ( 48 ) and HCC ( 49 ); thus, the mutation of the CSMD1 may cause the proliferation of the cancer. One published article revealed that the mutation of CSMD1 may promote the progression of esophageal cancer ( 50 ).…”

The Diverse Role of CUB and Sushi Multiple Domains 1 (CSMD1) in Human Diseases

“…The low expression of CSMD1 was also associated with reduced survival in the breast cancer METABRIC study [ 68 ]. Gialeli et al suggested that CSMD1 provides tumour suppression by interacting with the EGFR pathway and can be used as a biomarker for predicting chemotherapy response in highly invasive breast cancer [ 69 ]. Additionally, Tang et al discovered that the decreased expression of CSMD1 in melanoma cells has a lower influence on melanoma cell migration and proliferation, and that CSMD1 can serve as a tumour suppressor gene in melanoma cells [ 13 ].…”