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      Cadmium Malignantly Transforms Normal Human Breast Epithelial Cells into a Basal-like Phenotype

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          Abstract

          Background

          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.

          Methods

          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.

          Results

          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.

          Conclusions

          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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          Most cited references33

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          The changing global patterns of female breast cancer incidence and mortality

          One in ten of all new cancers diagnosed worldwide each year is a cancer of the female breast, and it is the most common cancer in women in both developing and developed areas. It is also the principal cause of death from cancer among women globally. We review the descriptive epidemiology of the disease, focusing on some of the key elements of the geographical and temporal variations in incidence and mortality in each world region. The observations are discussed in the context of the numerous aetiological factors, as well as the impact of screening and advances in treatment and disease management in high-resource settings.
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            Cadmium carcinogenesis.

            Cadmium is a heavy metal of considerable environmental and occupational concern. Cadmium compounds are classified as human carcinogens by several regulatory agencies. The most convincing data that cadmium is carcinogenic in humans comes from studies indicating occupational cadmium exposure is associated with lung cancer. Cadmium exposure has also been linked to human prostate and renal cancer, although this linkage is weaker than for lung cancer. Other target sites of cadmium carcinogenesis in humans, such as liver, pancreas and stomach, are considered equivocal. In animals, cadmium effectively induces cancers at multiple sites and by various routes. Cadmium inhalation in rats induces pulmonary adenocarcinomas, in accord with its role in human lung cancer. Cadmium can induce tumors and/or preneoplastic lesions within the rat prostate after ingestion or injection. At relatively high doses, cadmium induces benign testicular tumors in rats, but these appear to be due to early toxic lesions and loss of testicular function, rather than from a specific carcinogenic effect of cadmium. Like many other metals, cadmium salts will induce mesenchymal tumors at the site of subcutaneous (s.c.) or intramuscular (i.m.) injections, but the human relevance of these is dubious. Other targets of cadmium in rodents include the liver, adrenal, pancreas, pituitary, and hematopoietic system. With the exception of testicular tumors in rodents, the mechanisms of cadmium carcinogenesis are poorly defined. Cadmium can cause any number of molecular lesions that would be relevant to oncogenesis in various cellular model systems. Most studies indicate cadmium is poorly mutagenic and probably acts through indirect or epigenetic mechanisms, potentially including aberrant activation of oncogenes and suppression of apoptosis.
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              BRCA1 regulates human mammary stem/progenitor cell fate.

              Although it is well established that women with germ-line mutations in the BRCA1 gene have a greatly increased lifetime incidence of breast and ovarian cancer, the molecular mechanisms responsible for this tissue-specific carcinogenesis remain undefined. The majority of these breast cancers are of the basal-like phenotype characterized by lack of expression of ER, PR, and ERBB2. Because this phenotype has been proposed to resemble that of normal breast stem cells, we examined the role of BRCA1 in human mammary stem cell fate. Using both in vitro systems and a humanized NOD/SCID mouse model, we demonstrate that BRCA1 expression is required for the differentiation of ER-negative stem/progenitor cells to ER-positive luminal cells. Knockdown of BRCA1 in primary breast epithelial cells leads to an increase in cells displaying the stem/progenitor cell marker ALDH1 and a decrease in cells expressing luminal epithelial markers and estrogen receptor. In breast tissues from women with germ-line BRCA1 mutations, but not normal controls, we detect entire lobules that, although histologically normal, are positive for ALDH1 expression but are negative for the expression of ER. Loss of heterozygosity for BRCA1 was documented in these ALDH1-positive lobules but not in adjacent ALDH1-negative lobules. Taken together, these studies demonstrate that BRCA1 plays a critical role in the differentiation of ER-negative stem/progenitor cells to ER-positive luminal cells. Because BRCA1 also plays a role in DNA repair, our work suggests that loss of BRCA1 may result in the accumulation of genetically unstable breast stem cells, providing prime targets for further carcinogenic events.
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                Author and article information

                Journal
                Environ Health Perspect
                Environmental Health Perspectives
                National Institute of Environmental Health Sciences
                0091-6765
                1552-9924
                December 2009
                13 August 2009
                : 117
                : 12
                : 1847-1852
                Affiliations
                [1 ] 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, USA
                [2 ] Basic Science Program, SAIC-Frederick, Inc., Frederick, Maryland, USA
                Author notes
                Address correspondence to M. Waalkes, NCI at NIEHS, 111 Alexander Dr., Research Triangle Park, NC 27709 USA. Telephone: (919) 541-2328. Fax: (919) 541-3970. E-email: waalkes@ 123456niehs.nih.gov
                [*]

                Current address: Carcinogen Identification and Evaluation Unit, International Agency for Research on Cancer, Lyon, France.

                Article
                ehp-117-1847
                10.1289/ehp.0900999
                2799457
                20049202
                80462841-2057-40f5-812b-8f86b5fb6671
                This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.
                History
                : 19 May 2009
                : 13 August 2009
                Categories
                Research

                Public health
                estrogen receptor,basal-type,malignant transformation,cadmium,breast cancer
                Public health
                estrogen receptor, basal-type, malignant transformation, cadmium, breast cancer

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