Academic journal article Environmental Health Perspectives

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

Academic journal article Environmental Health Perspectives

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

Article excerpt

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 [micro]M) 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 metallo-proteinase-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-(X 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.

CONCLUSIONS: 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.

KEY WORDS: basal-type, breast cancer, cadmium, estrogen receptor, malignant transformation Environ Health Perspect 117:1847-1852 (2009). doi:10.1289/ehp.0900999 available via http://dx.doi.org/[Online 13 August 2009]

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Breast cancer is a common disease and a leading cause of cancer deaths in women (Bray et al. 2004; Parkin et al. 2005). However, the etiology of breast cancer remains incompletely defined. Evidence indicates that both endocrine and environmental factors play mechanistic roles in female breast cancer (Bray et al. 2004), and estrogenic hormones are implicated as major determinants of breast cancer risk (Bernstein 2002; Bray et al. 2004). Endogenous esrrogens impact normal breast growth and development, increasing proliferation of critical cell populations, whereas exogenous, pharmacologic estrogens and xenoestrogens likely contribute to accumulated breast cancer risk (Bernstein 2002; Bray et al. 2004). However, classical estrogens alone cannot account for all cases of human breast cancer (Coyle 2004).

Cadmium is a toxic metal and common environmental contaminant [International Agency for Research on Cancer (IARC) 1993; Waalkes 2003]. A human lung carcinogen, cadmium has several other target sites in rodents, including tissues considered endocrine sensitive (IARC 1993; Waalkes 2003). Recent data indicate that human cadmium exposure may be associated with female breast cancer (McElroy et al. 2006), although this initial, hypothesis-forming work does not allow for establishment of definitive causality. There are no corollary data showing carcinogenic activity for cadmium in female rodent mammary tissue, but it can cause mammary gland proliferation in mice (Johnson et al. 2003). Additional studies, including in vitro cancer model studies, are critical to clarify any role for cadmium in this important and deadly disease.

Cadmium probably acts in all stages of the oncogenic process, and acts through multiple, nonexclusive mechanisms such as oxidative stress, oncogene activation, apoprotic bypass, and altered DNA methylation (Waalkes 2003). …

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