Department of Clinical Sciences, Polytechnic University of Marche, 60100, Ancona, Italy.
Department of Biomedical Sciences and Public Health, Polytechnic University of Marche, 60100, Ancona, Italy.
Hum Cell. 2023 May;36(3):1108-1119. doi: 10.1007/s13577-023-00892-9. Epub 2023 Mar 10.
Triple negative breast cancer (TNBC) displays a high aggressive behavior, tendency to relapse and early metastasize, leading to poor prognosis. The lack of estrogen receptors, and human epidermal growth factor receptor 2, prevents the use of endocrine or molecular targeted therapy, being therapeutical options for TNBC managements mostly limited to surgery, radiotherapy and mainly chemotherapy. While an important number of TNBCs initially responds to chemotherapy, they are prone to develop chemoresistance over the time. Thus, there is an urgent need to identify novel molecular targets to improve the outcome of chemotherapy in TNBC. In this work we focused on the enzyme paraoxonase-2 (PON2) which has been reported to be overexpressed in several tumors contributing to cancer aggressiveness and chemoresistance. Through a case-control study, we analyzed PON2 immunohistochemical expression in breast cancer molecular subtypes Luminal A, Luminal B, Luminal B HER2+, HER2 + and TNBC. Subsequently, we evaluated the in vitro effect of PON2 downregulation on cell proliferation and response to chemotherapeutics. Our results showed that the PON2 expression levels were significantly upregulated in the infiltrating tumors related to the subtypes Luminal A, HER2+ and TNBC compared to the healthy tissue. Furthermore, PON2 downregulation led to a decrease in cell proliferation of breast cancer cells, and significantly enhanced the cytotoxicity of chemotherapeutics on the TNBC cells. Although further analyses are necessary to deeply understand the mechanisms by which the enzyme could participate to breast cancer tumorigenesis, our results seem to demonstrate that PON2 could represent a promising molecular target for TNBC treatment.
三阴性乳腺癌（TNBC）表现出高度侵袭性、复发和早期转移倾向，导致预后不良。缺乏雌激素受体和人表皮生长因子受体 2，阻止了内分泌或分子靶向治疗的使用，因此 TNBC 管理的治疗选择主要限于手术、放疗和主要化疗。虽然相当数量的 TNBC 最初对化疗有反应，但它们容易随着时间的推移产生化疗耐药性。因此，迫切需要确定新的分子靶点，以改善 TNBC 化疗的效果。在这项工作中，我们专注于酶对氧磷酶 2（PON2），它已被报道在几种肿瘤中过度表达，有助于肿瘤的侵袭性和化疗耐药性。通过病例对照研究，我们分析了 PON2 在乳腺癌分子亚型 Luminal A、Luminal B、Luminal B HER2+、HER2+和 TNBC 中的免疫组化表达。随后，我们评估了 PON2 下调对细胞增殖和对化疗药物反应的体外影响。我们的结果表明，与健康组织相比，与 Luminal A、HER2+和 TNBC 相关的浸润性肿瘤中 PON2 的表达水平显著上调。此外，PON2 下调导致乳腺癌细胞增殖减少，并显著增强了化疗药物对 TNBC 细胞的细胞毒性。尽管需要进一步分析以深入了解该酶如何参与乳腺癌的发生机制，但我们的结果似乎表明 PON2 可能是治疗 TNBC 的有前途的分子靶点。
