Abstract:
Introduction: TNBC is a highly advanced, molecular subtype of breast cancer, characterized by lack of gene expression
of the estrogen receptor, progesterone receptor and HEGF-2 (human epidermal growth factor receptor-2). Additionally,
patients with TNBC, the absence of particular therapeutic targets are associated with unfavorable clinical results, while the
high risk of metastasis and recurrence. There is increasing evidence that epigenetic modifications, such as methylation of
DNA and demethylation events, are important factors in the spread and development of TNBC, also in metastasis and
treatment resistance. While active demethylation of DNA through 5-hydroxymethyl-cytosine (5-hmC) has been connected
to chromatin remodeling and gene regulation, DNA methylation through 5-methyl-cytosine (5-mC) is a crucial mechanism
for silencing genes. Tumor suppressor genes, oncogenic signaling pathways, and all cellular differentiation pathways have
been linked to the abnormal levels of 5-mC and 5-hmC found in TNBC samples.
Method: The research investigated how DNA methylation and demethylation markers in tumor tissue affect the response
of TNBC patients to neoadjuvant chemotherapy (NACT) compared to those who did not receive NACT, while exploring
the relationship between 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC), revealing new insights into the
predictive significance of these epigenetic indicators. The study comprised 40 female patients with TNBC, where 15
underwent neoadjuvant chemotherapy (NACT) and 25 did not. Global DNA methylation and demethylation levels were
measured using an ELISA-based technique to investigate the content of 5-mC and 5-hmC levels in DNA extracted from
biopsy samples of patients receiving NACT and postoperative tissues from those without NACT.
Results: There was a significant positive correlation found between two global methylation markers (rs=0.929, p <
0.0001).Favorable association between 5-hmc and 5-mC was observed (rs= 0.017, p < 0.951 and rs= 0.069, p < 0.743,
respectively). Hence we propose that 5-methylcytosine and 5-hydroxymethylcytosine to be consider as key molecular
markers of pathogenesis of TNBC. Moreover, the findings support epigenetic interventions aimed to restore DNA
methylation dynamics to a "normal" state.
