School of Pharmaceutical Science and Technology (SPST), Tianjin University, Tianjin, China.
Guangzhou Institute of Oral Disease, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China.
Breast Cancer Res Treat. 2022 Jan;191(2):319-326. doi: 10.1007/s10549-021-06435-w. Epub 2021 Nov 1.
CYP4Z1 is a human cytochrome P450 enzyme involved in breast cancer progression and prognosis, but its functional role in these processes is not understood. In order to gain more insight into CYP4Z1's properties it was recombinantly expressed in a host animal that does not have an endogenous homologue.
We generated a transgenic mouse model that specifically expresses human CYP4Z1 in breast tissue under the control of the whey acidic protein promoter. Complementary experiments were done using cell lines derived from human breast cell.
Induction of CYP4Z1 expression led to reduction of body weight, activity, and birth rates. Histological analysis revealed no evidence for tumor formation. However, a strong increase in estrogen receptor alpha was observed by immunohistochemistry; weaker but significantly increased immunoreactivity was also detected for collagen I and fibronectin. Overexpression of CYP4Z1 in the human breast cancer cell line MCF7 also led to increased ERα expression. Moreover, increased expression of both CYP4Z1 and ERα was observed in MCF-10A normal breast cells upon cocultivation with MCF-7 cells (with or without overexpression of CYP4Z1).
These data suggest that CYP4Z1 facilitates breast cancer development by induction of ERα expression via an as yet undefined mechanism.
CYP4Z1 是一种参与乳腺癌发生和预后的人类细胞色素 P450 酶，但它在这些过程中的功能作用尚不清楚。为了更深入地了解 CYP4Z1 的特性，我们在一种没有内源性同源物的宿主动物中重组表达了它。
我们生成了一种转基因小鼠模型，该模型在乳清酸性蛋白启动子的控制下特异性地在乳腺组织中表达人 CYP4Z1。使用源自人乳腺细胞的细胞系进行了补充实验。
CYP4Z1 表达的诱导导致体重、活力和出生率下降。组织学分析没有发现肿瘤形成的证据。然而，免疫组织化学显示雌激素受体 α 强烈增加；胶原 I 和纤维连接蛋白的免疫反应也较弱但显著增加。CYP4Z1 在人乳腺癌细胞系 MCF7 中的过表达也导致 ERα 表达增加。此外，在 MCF-10A 正常乳腺细胞与 MCF-7 细胞共培养时（无论是否过表达 CYP4Z1），均观察到 CYP4Z1 和 ERα 的表达增加。
这些数据表明，CYP4Z1 通过未知机制诱导 ERα 表达促进乳腺癌的发展。
