Role of Sorcin and Annexin A3 in Breast Cancer Patients
Keywords
Abstract
Description
Breast cancer is the most common female malignancy worldwide. Despite advances in cancer diagnosis and treatment in recent years, traditional treatments (radiotherapy, chemotherapy, and hormone therapy) are always limited by the resistance of some tumor cells, thus forcing researchers to continue to look for new therapeutic approaches and targets. Soluble resistance-related Calcium-binding protein (Sorcin) is a penta-EF hand calcium binding protein, which participates in the regulation of calcium homeostasis in cells and has molecular mass of 22 kDa. The EF-hand is a common helix-loop-helix structural motif used by proteins to bind calcium. Most proteins are endowed with an even number of EF-hands, which are usually structurally and functionally paired. The penta-EF hand (PEF) family includes sorcin, calpains, programmed cell death protein 6 (PDCD6), peflin and grancalcin.
High sorcin regulates the calcium channels and exchangers located at the plasma membrane and at the endo/sarcoplasmic reticulum (ER/SR) and allows high levels of calcium in the ER to be maintained, preventing ER stress and the unfolded protein response, and increases escape from apoptosis. The 18-kDa variant of sorcin is regulated by Tumor necrosis factor receptor-associated protein 1 (TRAP1), a mitochondrial anti-apoptotic protein upregulated in several human tumors which controls sorcin folding and expression. Conversely, sorcin silencing activates apoptotic proteases as caspase-3 and caspase-12 results in major defects in mitosis and cytokinesis, blocks cell cycle progression in mitosis, increases the number of rounded polynucleated cells and induces apoptosis and cell death shifting the equilibrium between cell life and cell death towards proliferation in MDR cancer cells overexpressing sorcin.
Sorcin is highly expressed in the heart, brain and breast and overexpressed in many cancer cells. The gene for sorcin (SRI) spans about 21.9 kb of human genomic DNA. The gene is located in chromosome 7q21. Sorcin gene is in the same amplicon as other genes involved in the resistance to chemotherapeutics in cancer cells (multi-drug resistance, MDR) such as the ATP-binding cassette (ABC) transporters ABCB4 and ABCB1 (Mdr1, or P-glycoprotein 1).
Annexins are a family of intracellular proteins that bind membrane phospholipids in a Calcium concentration-dependent manner. The human genome encodes for 12 different annexins varying in expression and distribution within the tissues. Some of these are ubiquitously expressed (A1, A2, A5, A6, and A7), while some are selective (A3, A8, A9, A10, and A13). Several annexins play important roles during tumor progression. However, little is known about the clinical implications and biological functions of Annexin A3 (ANXA3) in breast cancer. ANXA3 has a role in cell differentiation, cell migration, immune regulation.
The ANXA3 gene is located on human chromosome 4q13-q22 and encodes a protein of 323 amino acid residues. Annexin A3 participates in various tumor-associated biological processes, including tumor initiation, progression, metastasis and is associated with chemotherapy resistance.
ANXA3 is expressed and secreted by neoplastic mammary cells, and its inhibition halts migration in breast cancer cells. The expression of Annexin A3 in human breast carcinoma closely correlated with tumor size and axillary lymph node metastasis. Elevated serum levels of ANXA3 protein were due to its increased secretion from neoplastic breast cells into the systemic circulation. There is inverse correlation between Annexin A3 expression and overall breast cancer patient survival. Moreover, Annexin A3 might be a novel and potential prognostic marker for patients with breast cancer and is involved in regulating apoptosis by affecting the Bcl-2/Bax balance. It promote the transcription of the anti-apoptotic gene Bcl-2 and downregulate the proapoptotic gene BAX.
Dates
Last Verified: | 12/31/2018 |
First Submitted: | 07/07/2018 |
Estimated Enrollment Submitted: | 07/22/2018 |
First Posted: | 07/25/2018 |
Last Update Submitted: | 01/07/2019 |
Last Update Posted: | 01/08/2019 |
Actual Study Start Date: | 01/19/2019 |
Estimated Primary Completion Date: | 07/31/2019 |
Estimated Study Completion Date: | 09/29/2019 |
Condition or disease
Intervention/treatment
Genetic: Sorcin gene expression
Other: Annexin A3 serum mesurement
Phase
Arm Groups
Arm | Intervention/treatment |
---|---|
Breast cancer patients The present study will be carried on 50 breast cancer patients before surgery.
The followings markers must be estimated:
Sorcin gene expression using real time PCR and Annexin A3 serum mesurement using enzyme linked immuno sorbent assay (ELISA). | |
Healthy controls The present study will be carried on 15 age and sex matched controls.
The followings markers must be estimated:
Sorcin gene expression using real time PCR and Annexin A3 serum mesurement using ELISA. | |
Benign breast diseases The present study will be carried on 15 patients with benign breast diseases.
The followings markers must be estimated:
Sorcin gene expression using real time PCR and Annexin A3 serum mesurement using ELISA. |
Eligibility Criteria
Ages Eligible for Study | 20 Years To 20 Years |
Sexes Eligible for Study | Female |
Sampling method | Probability Sample |
Accepts Healthy Volunteers | Yes |
Criteria | Inclusion Criteria: - breast cancer patients before surgery who are admitted to the South Egypt Cancer Institute, Surgery Department, Assiut University Exclusion Criteria: - • Patients with malignancies elsewhere in the body. - Patients with chronic cardiac diseases. - Getting neoadjuvant chemotherapy. - Renal disease. - Neurodegenerative disease. |
Outcome
Primary Outcome Measures
1. Role of SORCIN in patients with breast cancer [1 year]
Secondary Outcome Measures
1. Role of annexin A3 biomarker in with breast cancer patients [1 year]