Role of Tumor Suppressor protein CSMD1 along with its effect on Trastuzumab treatment in HER-2 positive Breast adenocarcinoma and its regulation by miRNAs in Gliomas

Abstract

Background: Cancer, which is known for its high mortality rate, can affect several tissue types. Among these, breast cancer is the most prevalent form worldwide and gliomas has one of the highest mortality rates among all cancer types. CSMD1 is a complement inhibitor with known tumor suppressor properties, whose down-regulation and deletion has been identified in several cancer types. In this study, we aim to investigate the role of CSMD1 in HER2-positive breast cancer and uncover its regulation in gliomas by miRNAs.

Methods: Patient data from SCAN-B cohort was used to determine the effect of CSMD1 on HER2-positive breast cancer. CSMD1 was introduced into SK-BR-3 cells and its effect was assessed using functional assays. We investigated the effect of CSMD1 on the dimerization of HER2 upon EGF stimulation and its effect on the ErbB signaling cascade. We also elucidated the role of CSMD1 in anti-HER2 therapy using trastuzumab. Patient data from CGGA and TCGA databases was used to determine the prognostic significance of miRNAs in patients with glioma. The effects of the miRNA expression on CSMD1 expression were quantified using qPCR. We also validated the effect of CSMD1 down-regulation using functional assays like proliferation, migration, invasion, and tumor sphere formation assays.

Results: Analysis of the SCAN-B patient data suggested that high expression of CSMD1 is associated with increased response to anti-HER2 therapy. CSMD1 inhibited the migration, invasion, and tumor sphere formation capabilities of SK-BR-3 cells and overexpression of CSMD1 inhibited EGFR dimerization and lead to an increase in inactive HER2 dimers, characterized by the inhibition of pHER2 upon EGF stimulation. Moreover, CSMD1 down-regulated the activation of the FAK signaling pathway, which is a downstream signaling pathway of HER2. Analysis of the CGGA and TCGA database resulted in identifying three potential CSMD1 regulating miRNA which are associated with poor prognosis in patients, among which up-regulation of miR-130b-3p down-regulated the expression of CSMD1 in H4 cells, while also increasing its cellular migration, invasion, and tumor sphere formation abilities.

Conclusion: Our study indicated that CSMD1 expression is related to favorable prognosis, and it is implicated in EGFR and HER2 dimerization in HER2-positive breast cancer. In glioma’s, CSMD1 is potentially down regulated by miR-130b-3p.

Popular Abstract

Role of complement inhibitor CSMD1 in Cancer:

Human Cub and Sushi multiple domain (CSMD1) is a complement protein which is gaining popularity in recent years due to its tumor suppressor function. The protein has increased interest after studies found its location on chromosome 8 frequently deleted in several cancer types like breast, liver, lung, colorectal and skin cancer. The initial evidence of its tumor suppressor properties was identified in melanoma and breast cancer cells, where high expression of CSMD1 led to decreased cancer progression. CSMD1 is also known to be highly expressed in the brain and recent studies have shown that lower CSMD1 expression in glioma is correlated to poor prognosis in patients.

CSMD1 in breast cancer:

Breast cancer is one of the most prevalent forms of cancer with the highest mortality rates among women. A recent study from the lab has shown that CSMD1 can improve the effect of chemotherapy in triple negative breast cancer. Based on the details of this study, we predict that CSMD1 could play an important role in HER2-positive breast cancer. HER2-positive breast cancer is one of the most aggressive forms of breast cancer with limited treatment options, along with resistance to existing treatment. Hence, there is need to improve and develop treatments and diagnostics. We hypothesize that CSMD1 could play a vital role to improve the already existing treatment options. To summarize, CSMD1 could prove to be a promising biomarker for the treatment of HER2-positive breast cancer.

CSMD1 in glioma:

Gliomas are the most common subtype of intracranial tumours. They are classified across four grades, from grade 1 to grade 4 in the order of least to most aggressive. Grade 4 gliomas are otherwise known as glioblastoma multiforme (GBM) and can form from lower grades of gliomas. The treatment of any intracranial tumours is having several challenges including the presence of the blood brain barrier (BBB). However, recent discoveries lead to the finding of dysregulation of miRNA expression between diseased and healthy tissue. MiRNA are small oligonucleotides that can regulate several genes and are not inhibited by the presence of the BBB. Several studies have shown that miRNA can regulate CSMD1 in various cancer types. Hence, we aim to investigate, whether the regulation of CSMD1 in gliomas are driven by miRNA dysregulation in glioma.

• author: Selvam, Mario Prateek
• supervisor: Anna Blom
• organization: Degree Projects in Molecular Biology
• course: MOBN03 20222
• year: 2023
• type: H2 - Master's Degree (Two Years)
• subject: Biology and Life Sciences
• language: English
• id: 9140662
• date added to LUP: 2023-10-31 11:33:03
• date last changed: 2023-10-31 11:33:03