The transcription factor Brother Regulator Of Imprinted Sites (BORIS), is a member of the testicular cancer antigen (CTA) family. It maps to chromosome number 20q13.2 and this region is genetically linked to early onset breast cancer. It uses different sets of zinc finger regions to mediate distinct functions in the regulation of gene expression. The BORIS gene is expressed during spermatogenesis in the testis as well as in various types of cancer, such as uterine, lung, stomach and breast cancers. It is indicated that BORIS can serve as a biomarker of breast cancer patients worldwide. High levels of BORIS protein are detected in leukocytes in breast cancer patients, suggesting that it may be used as an important biomarker for tumor progression.
In a joint study by Arab universities, researchers examined the important hotspot coding region of the BORIS gene for mutational analysis by the molecular PCR-SSCP technique in 155 female breast cancer patients. They found 25 missense mutations (16.12%) located in codon 329 leading to Valine>Isoleucine (G>A). Importantly, the BORIS sequence changes were exclusively associated with isolated breast cancer cells and were not found in adjacent normal tissues. The transition for G>A at the nucleotide position 6267 led to a change from valine to isoleucine in breast cancer patients, and this amino acid residue is evolutionarily conserved and this variant serves as a risk factor for tumor progression.
To elucidate the role of mutations in the BORIS gene in breast cancer progression, we revealed a significant association between the BORIS mutation and clinical stage, lymph node status, ER-alpha, PR-a expression, and cell status. patients menopause. More than 80% of the cases included in the survey showed moderate or high BORIS expression which was related to clinical/nodal stage and ER-alpha and PR-a receptor expression. Immunohistochemical staining of the biopsies revealed that BORIS protein levels were significantly higher in all breast tumors than normal. Mutation and protein expression analysis were combined and found a significant association in the high (+++) expression level category of BORIS, which shows a higher number of mutations.
Thus it appears that breast cancer progression was correlated with a higher level of BORIS expression and a greater number of mutations with disease progression. Therefore, BORIS is hypothesized to serve as a potential biomarker in breast cancer progression. But that’s not all, there are some teams of researchers trying to make a vaccine against this protein. For example, recently a team of iranian researchers used multiple immuno-computing approaches along with other computational approaches to design a novel multi-epitope breast cancer vaccine. The most immunogenic regions of the BORIS antigen were selected based on their binding affinity to MHC-I and II molecules containing multiple cytotoxic T lymphocyte (CTL) epitopes linked to a linker region.
Then, a T helper epitope (PADRE) and TLR-4/MD-2 agonist (Mycobacterium ribosomal protein L7/L12) were incorporated by the A(EAAAK)3A linker to form the final vaccine construct. This gave rise to a stable, immunogenic, and nonallergenic protein that contained several CTL epitopes, interferon-γ-inducing epitopes, and several linear and conformational B lymphocyte epitopes. Furthermore, the final vaccine construct formed stable and significant interactions. with the TLR-4/MD-2 receptor complex according to dynamic simulations. The idea has been made operational in laboratory mice, with a vaccine built against the mouse version of BORIS, which is the CTCF factor. The vaccine has been shown to be highly effective in treating aggressive breast cancer in the 4T1 mouse model.
Then the scientists further tested the therapeutic efficacy of BORIS in a 13762 rat breast cancer model, generating a replicon particle derived from Venezuelan equine encephalitis virus (recombinant VEE-VRP) that expresses the vector lacking a domain of DNA binding (VRP-mBORIS). Rats were inoculated with 13762 cells, immunized with VRP-mBORIS 48 hours later, and then boosted at 10-day intervals thereafter. The treated rats were repurposed with the same 13762 cells. BORIS was expressed in a small population of 13762 tumor stem cells. Treatment of rats with VRP-BORIS suppressed tumor growth leading to its complete disappearance in up to 50% of rats and significantly improved their survival. Re-challenge of rats treated with the same 13762 cells indicated that the immune response prevented tumor growth.
Attempts to make immunotherapy against the BORIS protein dates back more than 15 years ago, but the most successful attempts have succeeded in the last 5-6 years and will possibly be perfected, aided by the implementation of the latest molecular biology methods.
- A cura del Dr. Gianfrancesco Cormaci, PhD, specialista in Biochimica Clinica.
Akhtar MS et al. Oncotarget 2023 May 26; 14:528-541.
Zhou S et al. Cancer Gene Ther. 2023; 30(2):236-244.
Mahdevar M et al. J Biomol Struct Dyn 2022; 40(14):6363.
Akhter N et al. Eur Rev Med Pharm Sci. 2021; 25:4258.
Zhang Y, Song Y, Li C et al. Oncology Lett. 2020; 20:251.
Debruyne DN, Dries R et al. Nature. 2019; 572:676–80.