Expression of CYP1A1 and CYP1B1 depends on cell-specific factors in human breast cancer cell lines: role of estrogen receptor status
Expression of CYP1A1 and CYP1B1 depends on cell-specific factors in human breast cancer cell lines: role of estrogen receptor status
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DOI：
10.1093/carcin/20.6.947
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发表时间：
1999-06-01
期刊：
影响因子：
4.7
通讯作者：
Jefcoate, CR
中科院分区：
文献类型：
--
作者：
Angus, WGR;Larsen, MC;Jefcoate, CR
研究雌激素受体(ER)对两对ER+/ER-人乳腺上皮细胞系细胞色素P4501B1(CYP1B1)和细胞色素P4501A1(CYP1A1)表达和活性的影响。用抗雌激素的ICI182,780(ICI)评价ER的急性丢失，在所有细胞系中，CYP1B1呈结构性表达，且由2，3，7，8-四氯二苯并-对二恶英(TCDD)诱导，而CYP1A1仅在诱导后表达。T47D细胞中各CYP(有或无TCDD)的表达均高于MDA细胞。内质网以相反的方向影响这些基因的表达。ER表型与TCDD诱导的细胞色素P1A1表达减少有关，但基础和诱导的细胞色素P1B1表达增加。ICI处理ER+细胞48h后，P450的表达模式不能逆转为ER-细胞。根据重组酶的活性和表达水平，细胞株间7，2-二甲基苯并[α]菲(DMBA)代谢的差异与细胞色素P1A1和细胞色素P1B1表达的差异是一致的。在T47D株系中，根据区域选择性代谢物的分布和抗CYP1B1抗体的抑制(80%)，微粒体DMBA的基础代谢主要是由CYP1B1引起的。TCDD诱导的微粒体代谢主要由细胞色素P1A1引起，并被抗细胞色素P1A1抗体抑制50%，TCDD诱导的丙二醛(+)细胞表现为细胞色素P1A1活性，而TCDD诱导的丙二醛(-)细胞表现为细胞色素P1B1活性。芳香烃受体(AhR)水平，而不是AhR核转位蛋白(ARNT)水平高度依赖于细胞类型；AhR在MDA中高且不依赖ER，在T47D中低且ER连锁，AhR水平对ICI不敏感，ER不直接调节CYP1A1、CYP1B1或AhR的表达，实际上，在克隆选择过程中取代ER参与生长调控的因素占主导地位。每个细胞系特有的特性，包括内质网状态，决定了CYP1A1和CYP1B1的表达。
The impact of estrogen receptor (ER) was examined for expression and activity of cytochrome P4501B1 (CYP1B1) and cytochrome P4501A1 (CYP1A1) in two pairs of ER+/ER- human breast epithelial cell lines derived from single lineages, and representing earlier (T47D) or later (MDA-MB-231) stages of tumorigenesis. Acute loss of ER was evaluated using the anti-estrogen ICI 182,780 (ICI), In all lines, CYP1B1 was expressed constitutively and was induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), whereas CYP1A1 was expressed only following induction. Expression of each CYP (with or without TCDD) was greater in T47D cells than MDA cells. The ER impacted expression of these genes in opposite directions. The ER- phenotype was associated with less TCDD-induced CYP1A1 expression, but greater basal and induced CYP1B1 expression. A 48 h treatment of ER+ cells with ICI did not revert the P450 expression pattern to that of ER- cells. Based on activities of recombinant enzyme and expression levels, differences in 7,2-dimethylbenz [alpha]anthracene (DMBA) metabolism between the cell lines were consistent with differences in CYP1A1 and CYP1B1 expression. In T47D lines, basal microsomal DMBA metabolism was primarily due to CYP1B1, based on regioselective metabolite distribution and inhibition by anti-CYP1B1 antibodies (>80%). Metabolism in TCDD-induced microsomes was mostly due to CYP1A1 and was inhibited by anti-CYP1A1 antibody (>50%), TCDD-induced MDA(+) cells demonstrated CYP1A1 activity, whereas TCDD-induced MDA(-) cells displayed CYP1B1 activity. Aryl hydrocarbon receptor (AhR) levels, but not AhR nuclear translocator protein (ARNT) levels were highly dependent on cell type; AhR was high and ER-independent in MDA, and low and ER-linked in T47D, AhR levels were insensitive to ICI, ER does not directly modulate the expression of CYP1A1, CYP1B1 or AhR, Indeed, factors that have replaced ER in growth regulation during clonal selection predominate in this regulation. Characteristics unique to each cell line, including ER status, determine CYP1A1 and CYP1B1 expression.