de Sousa Pereira Nathália, Vitiello Glauco Akelinghton Freire, Amarante Marla Karine
Oncology Laboratory, Department of Pathology, Clinical and Toxicological Analyses, Health Sciences Center, Londrina State University, Londrina 86057-970, PR, Brazil.
Translational Immuno-Oncology Group, International Research Center, A.C. Camargo Cancer Center, São Paulo 01508-010, SP, Brazil.
Diagnostics (Basel). 2023 Mar 22;13(6):1196. doi: 10.3390/diagnostics13061196.
The association between mouse mammary tumor virus (MMTV)-like sequences and human breast cancer (BC) is largely documented in the literature, but further research is needed to determine how they influence carcinogenesis. APOBEC3 cytidine deaminases are viral restriction factors that have been implicated in cancer mutagenesis, and a germline deletion that results in the fusion of the APOBEC3A coding region with the APOBEC3B 3'-UTR has been linked to increased mutagenic potential, enhanced risk of BC development, and poor prognosis. However, little is known about factors influencing APOBEC3 family activation in cancer. Thus, we hypothesized that MMTV infection and APOBEC3-mediated mutagenesis may be linked in the pathogenesis of BC. We investigated genotyping, MMTV-like positivity, and clinicopathological parameters of 209 BC patients. We show evidence for active APOBEC3-mediated mutagenesis in human-derived MMTV sequences and comparatively investigate the impact of germline deletion in MMTV-like positive and negative BC in a Brazilian cohort. In MMTV-like negative samples, deletion was negatively correlated with tumor stage while being positively correlated with estrogen receptor expression. Although was not associated with MMTV-like positivity, samples carrying both MMTV-like positivity and APOBEC3A/B deletion had the lowest age-at-diagnosis of all study groups, with all patients being less than 50 years old. These results indicate that APOBEC3 mutagenesis is active against MMTV-like sequences, and that deletion might act along with the MMTV-like presence to predispose people to early-onset BC.
小鼠乳腺肿瘤病毒（MMTV）样序列与人类乳腺癌（BC）之间的关联在文献中已有大量记载，但仍需进一步研究以确定它们如何影响致癌作用。载脂蛋白B mRNA编辑酶催化多肽样3（APOBEC3）胞苷脱氨酶是病毒限制因子，与癌症诱变有关，一种导致APOBEC3A编码区与APOBEC3B 3'-非翻译区融合的种系缺失与诱变潜力增加、BC发生风险增强及预后不良有关。然而，关于影响癌症中APOBEC3家族激活的因素知之甚少。因此，我们推测MMTV感染与APOBEC3介导的诱变可能在BC的发病机制中存在关联。我们调查了209例BC患者的基因分型、MMTV样阳性情况及临床病理参数。我们展示了人类来源的MMTV序列中APOBEC3介导的活跃诱变的证据，并在巴西队列中比较研究了MMTV样阳性和阴性BC中种系缺失的影响。在MMTV样阴性样本中，缺失与肿瘤分期呈负相关，而与雌激素受体表达呈正相关。虽然缺失与MMTV样阳性无关，但同时携带MMTV样阳性和APOBEC3A/B缺失的样本在所有研究组中诊断时年龄最小，所有患者均小于50岁。这些结果表明，APOBEC3诱变对MMTV样序列具有活性，并且缺失可能与MMTV样序列的存在共同作用，使人们易患早发性BC。
