Clinical trial NCT03598660: Role of Sorcin and Annexin A3 in Breast Cancer Patients
Official title: Role of Sorcin and Annexin A3 in Breast Cancer Patients
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Breast Cancer
Keywords: Breast cancer, SORCIN, Annexin A3
Lead sponsor: Assiut University
Sponsor class: OTHER
First posted: 2018-07-26
Enrollment: 80
Sex: FEMALE
Minimum age (years): 20
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: CROSS_SECTIONAL
Sampling method: PROBABILITY_SAMPLE
Study population: breast cancer patients

Brief summary: Breast cancer (BC) is the most common female malignancy worldwide and the second leading cause of cancer death in women. One in eight women in the United States will develop the illness in their lifetimes. In Egypt, 37.7% of total cancer cases among women is breast cancer. A locally advanced disease is very common and total mastectomy is the most commonly performed surgery. Screening methods and adjuvant therapy following surgery led to a remarkable decrease in mortality.

Reliable prognostic and predictive markers are needed to guide the selection of the most appropriate adjuvant therapies for individual patients with breast cancer. In fact, a shift from defining the cancer patients who should receive chemotherapy on the basis of their prognostic characteristics to defining the patients who are likely to benefit most from this modality of adjuvant treatment is currently taking place. Understanding the molecular mechanisms underlying the spread of cancer cells to distant organs, therefore, is a prerequisite for the development of novel cancer therapies.

Detailed 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.

Eligibility 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.

Primary outcomes:
measure: Role of SORCIN in patients with breast cancer
timeFrame: 1 year
Secondary outcomes:
measure: Role of annexin A3 biomarker in with breast cancer patients
timeFrame: 1 year
Other outcomes:
Locations:
Study officials:
References:
citation: Zeeneldin AA, Ramadan M, Elmashad N, Fakhr I, Diaa A, Mosaad E. Breast cancer laterality among Egyptian patients and its association with treatments and survival. J Egypt Natl Canc Inst. 2013 Dec;25(4):199-207. doi: 10.1016/j.jnci.2013.09.003. Epub 2013 Oct 25.
citation: Cubasch H, Joffe M, Ruff P, Dietz D, Rosenbaum E, Murugan N, Chih MT, Ayeni O, Dickens C, Crew K, Jacobson JS, Neugut A. Breast conservation surgery versus total mastectomy among women with localized breast cancer in Soweto, South Africa. PLoS One. 2017 Aug 10;12(8):e0182125. doi: 10.1371/journal.pone.0182125. eCollection 2017.
citation: Colotti G, Poser E, Fiorillo A, Genovese I, Chiarini V, Ilari A. Sorcin, a calcium binding protein involved in the multidrug resistance mechanisms in cancer cells. Molecules. 2014 Sep 5;19(9):13976-89. doi: 10.3390/molecules190913976.
citation: Kim JY, Jung EJ, Park HJ, Lee JH, Song EJ, Kwag SJ, Park JH, Park T, Jeong SH, Jeong CY, Ju YT, Lee YJ, Hong SC. Tumor-Suppressing Effect of Silencing of Annexin A3 Expression in Breast Cancer. Clin Breast Cancer. 2018 Aug;18(4):e713-e719. doi: 10.1016/j.clbc.2017.11.009. Epub 2017 Nov 21.