Benbrahim-Tallaa Lamia, Tokar Erik J, Diwan Bhalchandra A, Dill Anna L, Coppin Jean-François, Waalkes Michael P
Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute (NCI) at National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA.
Environ Health Perspect. 2009 Dec;117(12):1847-52. doi: 10.1289/ehp.0900999. Epub 2009 Aug 13.
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-alpha 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-alpha negative.
Cadmium malignantly transforms normal human breast epithelial cells-through a mechanism not requiring ER-alpha-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.
乳腺癌最近被认为与镉暴露有关。尽管并非完全得到证实，但据推测，镉通过雌激素受体（ER）发挥金属雌激素致癌作用。因此，我们研究了长期暴露于镉对人正常乳腺上皮细胞系MCF-10A的影响，该细胞系ER阴性，但在恶性转化过程中可转变为ER阳性。
将细胞持续暴露于低水平镉（2.5μM），并通过体外实验和异种移植研究检查恶性转化迹象。通过对乳腺癌关键基因的蛋白质和转录分析对转化细胞进行分子特征鉴定。
在镉暴露超过40周后，细胞表现出基质金属蛋白酶-9分泌增加、接触抑制丧失、集落形成增加以及侵袭性增强，这些都是癌细胞的典型特征。将经镉处理的细胞接种到小鼠体内可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HER2（人表皮生长因子受体2）阴性、BRCA1（乳腺癌易感基因1）表达降低以及CK5（细胞角蛋白5）和p63表达增加。CK5和p63均为乳腺干细胞标志物，在CTBE细胞团中显著过表达，表明持续增殖。CTBE细胞表现出全基因组DNA低甲基化以及c-myc和k-ras过表达，这在侵袭性乳腺癌中很典型。CTBE细胞异种移植肿瘤也为ER-α阴性。
镉通过一种不依赖ER-α的机制将正常人乳腺上皮细胞恶性转化为基底样癌表型。镉直接诱导人乳腺上皮细胞出现恶性表型有力地证明了其在乳腺癌发生中的潜在作用。
