Department of Pathology, Tohoku University Graduate School of Medicine, Miyagi, Japan; Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori, Japan.
Department of Pathology, Tohoku University Graduate School of Medicine, Miyagi, Japan; Department of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Miyagi, Japan.
J Steroid Biochem Mol Biol. 2022 Jul;221:106103. doi: 10.1016/j.jsbmb.2022.106103. Epub 2022 Mar 31.
Obesity has been known to increase the risks of breast cancer (BC) development and also to be associated with adverse clinical outcome of the patients. Abnormalities of cholesterol metabolism are not only related to obesity but also to biological or clinical behavior of BC patients. However, which metabolites or pathways of cholesterol metabolism could represent the characteristics of BC patients have remained virtually unknown. Therefore, in this study, we attempted to perform bird's eye view or comprehensive analysis of in situ or intra-tumoral cholesterol metabolic pathways using the multimodal approaches in order to elucidate the possible significance of cholesterol metabolites and its metabolic enzymes including CYP27A1, CYP7A1, and CYP46A1. GC-MS study using BC specimens was first performed in 60 BCE patients to evaluate cholesterol metabolism from cholesterol through oxysterols in both BC and normal tissues. Results of those analyses above lead to evaluating immunoreactivity and mRNA expression of CYP27A1, CYP7A1 and CYP46A1 in 213 and 153 BCE cases, respectively. Results of comprehensive GC-MS analysis did reveal that three oxysterols, 27-HC, 7α-HC and 24-HC were all related to malignant phenotypes in BC. 27-HC abundance was significantly associated with higher tumor stage (P = 0.0475) of BC patients. Luminal B type BC patients harboring high CYP27A1, the enzyme responsible for production of 27-HC were significantly associated with worse disease-free survival than those with low CYP27A1 (P = 0.0463). 7α-HC tended to be more abundant in HER2 positive and TNBC subtypes and higher levels of 7α-HC were also significantly associated with higher Ki-67 labeling index (P = 0.0022) and histological grade (P = 0.0286). CYP7A1, the enzyme involved in production of 7α-HC, was significantly more abundant in TNBC than other subtypes (vs Luminal A; P = 0.0321, vs Luminal B; P = 0.0048, vs HER2; P = 0.0103). The levels of 24-HC in BC were lower than normal breast tissues regardless of its subtypes. CYP46A1, the enzyme involved in the production of 24-HC, was detected only in 33 (15.5%) out of 213 BCE cases examined in this study. Results of our bird's eye view analysis of in situ or intra-tumoral cholesterol metabolism in BC patients did firstly reveal BC subtype dependent involvement of its different pathways. Results also indicated the therapeutic possibility of subtype dependent modification of cholesterol metabolizing pathways in BC patients.
肥胖已知会增加乳腺癌（BC）发展的风险，并且与患者的不良临床结局相关。胆固醇代谢异常不仅与肥胖有关，而且与 BC 患者的生物学或临床行为有关。然而，胆固醇代谢的哪些代谢物或途径可以代表 BC 患者的特征，实际上仍不清楚。因此，在这项研究中，我们试图使用多模态方法全面分析原位或肿瘤内胆固醇代谢途径，以阐明胆固醇代谢酶及其代谢产物 CYP27A1、CYP7A1 和 CYP46A1 的可能意义。首先对 60 例 BCE 患者的 BC 标本进行 GC-MS 研究，以评估 BC 和正常组织中胆固醇通过氧化固醇的代谢。对这些分析结果的评估导致分别对 213 例和 153 例 BCE 病例进行 CYP27A1、CYP7A1 和 CYP46A1 的免疫反应性和 mRNA 表达评估。综合 GC-MS 分析结果显示，三种氧化固醇 27-HC、7α-HC 和 24-HC 均与 BC 中的恶性表型有关。27-HC 丰度与 BC 患者较高的肿瘤分期显著相关（P=0.0475）。高 CYP27A1 （负责生成 27-HC 的酶）的管腔 B 型 BC 患者的无病生存显著低于低 CYP27A1 的患者（P=0.0463）。7α-HC 倾向于在 HER2 阳性和 TNBC 亚型中更丰富，较高水平的 7α-HC 也与较高的 Ki-67 标记指数（P=0.0022）和组织学分级（P=0.0286）显著相关。参与生成 7α-HC 的酶 CYP7A1 在 TNBC 中明显高于其他亚型（与管腔 A 相比；P=0.0321，与管腔 B 相比；P=0.0048，与 HER2 相比；P=0.0103）。BC 中的 24-HC 水平低于正常乳腺组织，无论其亚型如何。本研究共检查了 213 例 BCE 病例，其中仅在 33 例（15.5%）中检测到参与 24-HC 生成的酶 CYP46A1。我们对 BC 患者原位或肿瘤内胆固醇代谢的鸟瞰分析结果首次揭示了不同途径的 BC 亚型依赖性参与。结果还表明，在 BC 患者中，根据亚型依赖性改变胆固醇代谢途径具有治疗可能性。
