Breast Unit, DAME, University Hospital of Udine, Piazza Santa Maria della Misericordia, 15, 33100, Udine, Italy.
Ennergi Research (non-profit organisation), 33050, Lestizza, UD, Italy.
BMC Cancer. 2021 Oct 18;21(1):1118. doi: 10.1186/s12885-021-08844-y.
Breast cancer chemoresistance is attributed to a wide variety of mechanisms, including autophagy. Transcription factor EB (TFEB) has been recently identified and characterized as one major regulator of autophagy and lysosomal genesis.
This study aims to evaluate the prognostic impact of TFEB and its pathway in breast cancer chemoresistance.
This retrospective study analyzes the expression of TFEB, CARM1, SIRT1, and Beclin-1 and the methylation of PITX2 in breast carcinoma. A group of breast cancer patients treated with chemotherapy, who relapsed within 12 months from treatment initiation, were compared to a sub-cohort of chemo-treated patients who did not recur within 12 months of follow-up. The expression of TFEB, CARM1, SIRT1, and Belcin-1 was analyzed using immunohistochemistry or RT-PCR on formalin-fixed paraffin-embedded samples. PITX2 methylation was tested with the diagnostic CE-marked kit Therascreen PITX2 RGQ PCR. In the final model, 136 cases of chemo-treated breast cancer were included.
A higher TFEB and Beclin-1 expression correlate with shorter survival in patients with chemo-treated invasive breast cancer (respectively HR 3.46, CI.95 1.27-9.47, p < 0.05 and 7.11, CI.95 2.54-19.9). TFEB, CARM1, and SIRT1 are positively correlated with Beclin-1. The protein expression of SIRT1 is significantly associated with TFEB and CARM1 so that a very low SIRT1 expression (lower than the first quartile of the H-score distribution) correlates with a low expression of TFEB and CARM1 and with longer survival. SIRT1 seems to have a lower H-score in the basal-like and HER2-enriched tumors than the luminal subtypes. Beclin-1 and TFEB seem to have a higher H-score in the basal-like and HER2-enriched tumors than the luminal subtypes. PITX2 methylation analysis was feasible only in 65% of the selected samples, but no significant differences between cases and controls were found, and there was also no correlation with the expression of the TFEB pathway.
TFEB, SIRT1, and Beclin-1 seem to have a potential prognostic significance in patients with chemo-treated breast cancer, likely because of their role in the regulation of autophagy. In addition, no correlation between TFEB and PITX2 methylation was found, likely because they perform two different roles within the autophagy process.
乳腺癌的化疗耐药性归因于多种机制，包括自噬。转录因子 EB（TFEB）最近被鉴定并被确定为自噬和溶酶体发生的主要调节因子之一。
本研究旨在评估 TFEB 及其途径在乳腺癌化疗耐药性中的预后影响。
本回顾性研究分析了乳腺癌中 TFEB、CARM1、SIRT1 和 Beclin-1 的表达以及 PITX2 的甲基化。一组接受化疗的乳腺癌患者，在治疗开始后 12 个月内复发，与亚组接受化疗且在 12 个月随访内未复发的患者进行比较。使用福尔马林固定石蜡包埋样本的免疫组织化学或 RT-PCR 分析 TFEB、CARM1、SIRT1 和 Belcin-1 的表达。使用经过诊断认证的 Therascreen PITX2 RGQ PCR 试剂盒检测 PITX2 甲基化。在最终模型中，纳入了 136 例接受化疗的乳腺癌病例。
在接受化疗的浸润性乳腺癌患者中，TFEB 和 Beclin-1 表达较高与生存时间较短相关（分别为 HR 3.46，CI.95 1.27-9.47，p<0.05 和 7.11，CI.95 2.54-19.9）。TFEB、CARM1 和 SIRT1 与 Beclin-1 呈正相关。SIRT1 的蛋白表达与 TFEB 和 CARM1 显著相关，因此 SIRT1 表达非常低（低于 H 评分分布的第一四分位数）与 TFEB 和 CARM1 表达较低以及生存时间较长相关。SIRT1 在基底样和 HER2 富集型肿瘤中的 H 评分似乎低于管腔亚型。Beclin-1 和 TFEB 在基底样和 HER2 富集型肿瘤中的 H 评分似乎高于管腔亚型。仅对选定样本的 65%进行了 PITX2 甲基化分析，但未发现病例与对照组之间存在显著差异，也未发现与 TFEB 途径表达之间存在相关性。
TFEB、SIRT1 和 Beclin-1 似乎在接受化疗的乳腺癌患者中有潜在的预后意义，可能是因为它们在自噬调节中的作用。此外，未发现 TFEB 与 PITX2 甲基化之间存在相关性，可能是因为它们在自噬过程中发挥着两种不同的作用。
