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Complement inhibitor CSMD1 acts as tumor suppressor in human breast cancer
Astrid Escudero-Esparza1, Michael Bartoschek2, Chrysostomi Gialeli1
1Department of Translational Medicine, Lund University, Malmö, Sweden.
Abstract:
Human CUB and Sushi multiple domains 1 (CSMD1) is a membrane-bound complement inhibitor suggested to act as a putative tumor suppressor gene, since allelic loss of this region encompassing 8p23 including CSMD1 characterizes various malignancies. Here, we assessed the role of CSMD1 as a tumor suppressor gene in the development of breast cancer in vitro and in vivo. We found that human breast tumor tissues expressed CSMD1 at lower levels compared to that in normal mammary tissues. The decreased expression of CSMD1 was linked to a shorter overall survival of breast cancer patients. We also revealed that expression of CSMD1 in human breast cancer cells BT-20 and MDA-MB-231 significantly inhibited their malignant phenotypes, including migration, adhesion and invasion. Conversely, stable silencing of CSMD1 expression in T47D cells enhanced cancer cell migratory, adherent and clonogenic abilities. Moreover, expression of CSMD1 in the highly invasive MDA-MB-231 cells diminished their signaling potential as well as their stem cell-like properties as assessed by measurement of aldehyde dehydrogenase activity. In a xenograft model, expression of CSMD1 blocked the ability of cancer cells to metastasize to secondary sites in vivo, likely via inhibiting local invasion but not the extravasation into distant tissues. Taken together, these findings demonstrate the role of CSMD1 as a tumor suppressor gene in breast cancer.
Insights
Human CUB and Sushi multiple domains 1 (CSMD1) acts as a tumor suppressor in breast cancer. Lower CSMD1 levels correlate with poorer survival, and its expression inhibits cancer cell malignancy and metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Human CUB and Sushi multiple domains 1 (CSMD1) is a membrane protein implicated as a tumor suppressor due to its location on chromosome 8p23, a region frequently lost in various cancers.
- Allelic loss in the 8p23 region, including CSMD1, is associated with several malignancies, suggesting its potential role in cancer development.
Purpose of the Study:
- To investigate the role of CSMD1 as a tumor suppressor gene in breast cancer development.
- To evaluate the impact of CSMD1 expression on breast cancer cell phenotypes and metastasis in vitro and in vivo.
Main Methods:
- Comparative analysis of CSMD1 expression in normal mammary tissues versus human breast tumor tissues.
- In vitro studies involving forced expression or silencing of CSMD1 in breast cancer cell lines (BT-20, MDA-MB-231, T47D) to assess effects on migration, adhesion, invasion, and stem cell properties.
- In vivo xenograft mouse models to evaluate the effect of CSMD1 expression on metastasis.
Main Results:
- Human breast tumor tissues exhibited significantly lower CSMD1 expression compared to normal mammary tissues.
- Decreased CSMD1 expression was correlated with shorter overall survival in breast cancer patients.
- Overexpression of CSMD1 in BT-20 and MDA-MB-231 cells suppressed malignant phenotypes (migration, adhesion, invasion) and stem cell-like properties.
- Silencing CSMD1 in T47D cells enhanced migratory, adherent, and clonogenic abilities.
- In vivo, CSMD1 expression inhibited cancer cell metastasis in a xenograft model, primarily by reducing local invasion.
Conclusions:
- CSMD1 functions as a tumor suppressor gene in breast cancer.
- Reduced CSMD1 expression is a potential biomarker for poor prognosis in breast cancer patients.
- Modulating CSMD1 expression may offer a therapeutic strategy for inhibiting breast cancer progression and metastasis.
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