Cadmium malignantly transforms normal human breast epithelial cells into a basal-like phenotype.
Cadmium malignantly transforms normal human breast epithelial cells into a basal-like phenotype.
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DOI：
10.1289/ehp.0900999
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发表时间：
2009-12
影响因子：
10.4
通讯作者：
Waalkes MP
中科院分区：
文献类型：
--
作者：
Benbrahim-Tallaa L;Tokar EJ;Diwan BA;Dill AL;Coppin JF;Waalkes MP
乳腺癌最近与镉暴露有关。虽然没有统一的支持，它是假设镉作为一种金属雌激素致癌物通过雌激素受体（ER）。因此，我们研究了慢性接触镉对正常人乳腺上皮细胞系MCF-10A的影响，MCF-10A是ER阴性的，但在恶性转化过程中可以转化为ER阳性。将细胞连续暴露于低水平镉（2.5 μM），并在体外和异种移植研究中检查恶性转化的迹象。通过蛋白质和乳腺癌关键基因的转录本分析对转化细胞进行分子表征。超过40周的镉暴露，细胞表现出增加的基质金属蛋白酶-9分泌，接触抑制的损失，增加的集落形成，并增加侵袭，所有典型的癌细胞。将镉处理的细胞接种到小鼠体内产生具有肌上皮成分的侵袭性、转移性间变性癌。这些镉转化的乳腺上皮（CTBE）细胞表现出基底样乳腺癌的特征，包括ER-α阴性和HER 2（人表皮生长因子受体2）阴性，BRCA 1（乳腺癌易感基因1）表达减少，CK 5（细胞角蛋白5）和p63表达增加。CK 5和p63这两种乳腺干细胞标志物在CTBE细胞土丘中显著过表达，表明持续增殖。CTBE细胞表现出整体DNA低甲基化和c-myc和k-ras过表达，这在侵袭性乳腺癌中是典型的。CTBE细胞异种移植瘤也是ER-α阴性的。镉通过一种不需要ER-α的机制将正常的人类乳腺上皮细胞恶性转化为基底样癌表型。直接镉诱导人类乳腺上皮细胞的恶性表型，强烈强化了在乳腺癌中的潜在作用。
Breast cancer has recently been linked to cadmium exposure. Although not uniformly supported, it is hypothesized that cadmium acts as a metalloestrogenic carcinogen via the estrogen receptor (ER). Thus, we studied the effects of chronic exposure to cadmium on the normal human breast epithelial cell line MCF-10A, which is ER-negative but can convert to ER-positive during malignant transformation. Cells were continuously exposed to low-level cadmium (2.5 μM) and checked in vitro and by xenograft study for signs of malignant transformation. Transformant cells were molecularly characterized by protein and transcript analysis of key genes in breast cancer. Over 40 weeks of cadmium exposure, cells showed increasing secretion of matrix metalloproteinase-9, loss of contact inhibition, increased colony formation, and increasing invasion, all typical for cancer cells. Inoculation of cadmium-treated cells into mice produced invasive, metastatic anaplastic carcinoma with myoepithelial components. These cadmium-transformed breast epithelial (CTBE) cells displayed characteristics of basal-like breast carcinoma, including ER-α negativity and HER2 (human epidermal growth factor receptor 2) negativity, reduced expression of BRCA1 (breast cancer susceptibility gene 1), and increased CK5 (cytokeratin 5) and p63 expression. CK5 and p63, both breast stem cell markers, were prominently overexpressed in CTBE cell mounds, indicative of persistent proliferation. CTBE cells showed global DNA hypomethylation and c-myc and k-ras overexpression, typical in aggressive breast cancers. CTBE cell xenograft tumors were also ER-α negative. Cadmium malignantly transforms normal human breast epithelial cells—through a mechanism not requiring ER-α—into a basal-like cancer phenotype. Direct cadmium induction of a malignant phenotype in human breast epithelial cells strongly fortifies a potential role in breast cancer.
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女性乳腺癌发病率和死亡率的全球模式不断变化。
影响因子：
7.4
作者：
Bray, F;McCarron, P;Parkin, DM
通讯作者：
Parkin, DM
DOI：
10.1073/pnas.0711613105
发表时间：
2008-02-05
影响因子：
11.1
作者：
Liu, Suling;Ginestier, Christophe;Wicha, Max S.
通讯作者：
Wicha, Max S.
影响因子：
254.7
作者：
Parkin, DM;Bray, F;Pisani, P
通讯作者：
Pisani, P
DOI：
10.1385/scr:1:3:207
发表时间：
2005-01-01
期刊：
STEM CELL REVIEWS
影响因子：
--
作者：
Dontu, Gabriela;Liu, Suling;Wicha, Max S.
通讯作者：
Wicha, Max S.
影响因子：
3.6
作者：
Le Guével, R;Petit, FG;Pakdel, F
通讯作者：
Pakdel, F