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Cadmium promotes breast cancer cell proliferation by potentiating the interaction between ERalpha and c-Jun.

ABSTRACT: Cadmium is an environmental contaminant that enters the body through diet or cigarette smoke. It affects multiple cellular processes, including cell proliferation, differentiation, and apoptosis. Recently, cadmium has been shown to function as an endocrine disruptor, to stimulate estrogen receptor alpha (ERalpha) activity and promote uterine and mammary gland growth in mice. Although cadmium exposure has been associated with the development of breast cancer, the mechanism of action of cadmium remains unclear. To address this deficit, we examined the effects of cadmium treatment on breast cancer cells. We found that ERalpha is required for both cadmium-induced cell growth and modulation of gene expression. We also determined that ERalpha translocates to the nucleus in response to cadmium exposure. Additionally, we provide evidence that cadmium potentiates the interaction between ERalpha and c-Jun and enhances recruitment of this transcription factor complex to the proximal promoters of cyclin D1 and c-myc, thus increasing their expression. This study provides a mechanistic link between cadmium exposure and ERalpha and demonstrates that cadmium plays an important role in the promotion of breast cancer.

SUBMITTER: Siewit CL

PROVIDER: S-EPMC2870938 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Cadmium promotes breast cancer cell proliferation by potentiating the interaction between ERalpha and c-Jun.

Siewit Christina L CL Gengler Bridget B Vegas Esera E Puckett Rachel R Louie Maggie C MC

Molecular endocrinology (Baltimore, Md.) 20100310 5

Cadmium is an environmental contaminant that enters the body through diet or cigarette smoke. It affects multiple cellular processes, including cell proliferation, differentiation, and apoptosis. Recently, cadmium has been shown to function as an endocrine disruptor, to stimulate estrogen receptor alpha (ERalpha) activity and promote uterine and mammary gland growth in mice. Although cadmium exposure has been associated with the development of breast cancer, the mechanism of action of cadmium re ...[more]

PMID: 20219890

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Project description:BackgroundNucleosome assembly protein 1-like 1 (NAP1L1) is highly expressed in various types of cancer and plays an important role in carcinogenesis, but its specific role in tumor development and progression remains largely unknown. In this study, we suggest the potential of NAP1L1 as a prognostic biomarker and therapeutic target for the treatment of ovarian cancer (OC).MethodsIn our study, a tissue microarray (TMA) slide containing specimens from 149 patients with OC and 11 normal ovarian tissues underwent immunohistochemistry (IHC) to analyze the correlation between NAP1L1 expression and clinicopathological features. Loss-of- function experiments were performed by transfecting siRNA and following lentiviral gene transduction into SKOV3 and OVCAR3 cells. Cell proliferation and the cell cycle were assessed by the Cell Counting Kit-8, EDU assay, flow cytometry, colony formation assay, and Western blot analysis. In addition, co-immunoprecipitation (Co-IP) and immunofluorescence assays were performed to confirm the relationship between NAP1L1 and its potential targets in SKOV3/OVCAR3 cells.ResultsHigh expression of NAP1L1 was closely related to poor clinical outcomes in OC patients. After knocking down NAP1L1 by siRNA or shRNA, both SKOV3 and OVCAR3 cells showed inhibition of cell proliferation, blocking of the G1/S phase, and increased apoptosis in vitro. Mechanism analysis indicated that NAP1L1 interacted with hepatoma-derived growth factor (HDGF) and they were co-localized in the cytoplasm. Furthermore, HDGF can interact with jun proto-oncogene (C-JUN), an oncogenic transformation factor that induces the expression of cyclin D1 (CCND1). Overexpressed HDGF in NAP1L1 knockdown OC cells not only increased the expression of C-JUN and CCND1, but it also reversed the suppressive effects of si-NAP1L1 on cell proliferation.ConclusionsOur data demonstrated that NAP1L1 could act as a prognostic biomarker in OC and can interact with HDGF to mediate the proliferation of OC, and this process of triggered proliferation may contribute to the activation of HDGF/C-JUN signaling in OC cells.

Dataset Information

Cadmium promotes breast cancer cell proliferation by potentiating the interaction between ERalpha and c-Jun.

Publications

Cadmium promotes breast cancer cell proliferation by potentiating the interaction between ERalpha and c-Jun.

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