Page 113 - SRPSKO DRUŠTVO ISTRAŽIVAČA RAKA

SDIRSACR Oncology Insights

β-E6s preferentially bind MAML1, a transcriptional co-activator that plays a role in the Notch signalling pathway. This
interaction inhibits the expression of the Notch signalling target genes, consequently slowing down the differentiation
of infected keratinocytes. Notably, our recent analyses have shown that multiple α-E6s also bind MAML1, which results
in increased E6 stability. In the current study, we aimed to broaden our understanding of the reported α-E6-MAML1
interaction and test whether it is also implicated in the inhibition of the Notch signalling pathway and keratinocyte
differentiation.
Materials and Methods: GST pull-down and co-immunoprecipitation assays were employed to compare the binding
affinities among the E6 proteins from HPV types 8, 16, and 18 towards MAML1. To verify the effects of 16 E6 and 18 E6
on the expression of Notch-responsive genes, luciferase assays and qPCR were performed, with 8 E6 serving as a positive
control. Moreover, differentiation assays were carried out in keratinocytes that stably express the abovementioned E6
proteins.
Results: According to our data, cells exhibited reduced expression of Notch-responsive genes in the presence of MAML1-
binding α-E6s. Likewise, the expression of differentiation markers was decreased in these cells during differentiation
assays.
Conclusions: These preliminary results indicate that, besides β-E6s, α-E6 oncoproteins are also likely to inhibit the
Notch signalling pathway by associating with MAML1, consequently downregulating cellular differentiation.

P16

SIRT7 Overexpression as a Prognostic Indicator in Triple-Negative Breast Cancer

Bojana Uzelac , Ana Krivokuca , Snežana Susnjar , Zorka Milovanovic , GordanaSupic 1,2
3
3
1,2
3
¹Institute for Medical Research, Military Medical Academy, Crnotravska 17, 11 000 Belgrade, Serbia
2Medical Faculty of Military Medical Academy, University of Defense, Crnotravska 17, 11 000 Belgrade, Serbia
3Institute for Oncology and Radiology of Serbia, Pasterova 14, 11 000 Belgrade, Serbia

Keywords: Sirtuin7 Histone Deacetylases Triple Negative Breast Neoplasms

Background: Epigenetic regulation plays a key role in cancer by altering gene expression without changing the DNA
sequence. Recent advances highlight chromatin-modifying enzymes as promising biomarkers and therapeutic targets.
Among these, the sirtuin family has gained attention. Sirtuin 7 (SIRT7) is notable for its selective deacetylation of histone
H3 at lysine 18 (H3K18ac), an epigenetic mark linked to transcriptional repression and oncogenic transformation.
Although SIRT7 is involved in DNA repair, ribosome biogenesis, and metabolism, its clinical relevance in breast cancer
subtypes remains unclear. Investigating its expression may inform new therapeutic strategies, particularly for subtypes
lacking targeted treatments.
Patients and Methods: This study analysed SIRT7 expression in tumor tissues from 111 breast cancer patients, including
48 with triple-negative breast cancer (TNBC) and 63 with hormone receptor-positive, HER2-negative (ER+PR+HER2−)
tumors. Total RNA was extracted, and SIRT7 expression was quantified via real-time qPCR, normalized to reference
genes. Statistical analyses compared expression between subtypes and evaluated correlations with clinicopathological
features. Kaplan–Meier analysis assessed the association between SIRT7 expression and overall survival.
Results: No significant difference in SIRT7 expression was found between the subtypes. However, in the TNBC group,
SIRT7 overexpression was significantly associated with shorter overall survival (p = 0.037). The mean survival was 39
months for the high-expression group versus 52 months for the low-expression group. No survival correlation was
observed in the ER+PR+HER2− group. Additionally, in TNBC, high SIRT7 expression was associated with tumors smaller
than 2 cm.
Conclusions: SIRT7 overexpression correlates with worse survival in TNBC, suggesting its potential role as a prognostic
biomarker and a candidate for future targeted therapies. These findings support further investigation into SIRT7’s role
in epigenetic-based treatment strategies, particularly for aggressive and treatment-resistant breast cancers like TNBC.

Acknowledgments and funding: This research was conducted within the project MFVMA/02/20-22, "Genetic and
Epigenetic Variations in Genes Involved in Antitumor Immune Response in Solid Tumors," funding by the Ministry of
Defence.

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