Promotion of breast cancer by β-Hexachlorocyclohexane in MCF10AT1 cells and MMTV-neu mice
<p>Abstract</p> <p>Background</p> <p>Exposure to β-Hexachlorocyclohexane (β-HCH), a contaminant of the hexachlorohexane pesticide lindane, has been implicated as a risk factor in the development of breast cancers in epidemiological studies. Previous studies in our labor...
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| Format: | Article |
| Language: | English |
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BMC
2007-07-01
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| Series: | BMC Cancer |
| Online Access: | http://www.biomedcentral.com/1471-2407/7/130 |
| _version_ | 1811319020451790848 |
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| author | Matsumura Fumio Wong Patrick S |
| author_facet | Matsumura Fumio Wong Patrick S |
| author_sort | Matsumura Fumio |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Exposure to β-Hexachlorocyclohexane (β-HCH), a contaminant of the hexachlorohexane pesticide lindane, has been implicated as a risk factor in the development of breast cancers in epidemiological studies. Previous studies in our laboratory have demonstrated the ability of β-HCH to elicit its actions via a ligand-independent activation of the estrogen receptor through increased c-Neu (= erbB<sub>2 </sub>or HER-2) expression and kinase activation in both the BG-1 and MCF-7 cell lines. In addition, long term exposure (33 passages) to β-HCH was shown to promote the selection of MCF-7 cells which exhibit a more metastatic phenotype.</p> <p>Methods</p> <p>In this current study, we decided to investigate the long-term effects of β-HCH in both the MCF10AT1 cell line which was derived from a normal epithelial cell line by stably transfecting a mutated c-Ha-ras and a MMTV-Neu mouse model for mammary cancer <it>in vivo</it>. MCF10AT1 cells were exposed for 20 passages with β-HCH, 4-OH-Tamoxifen (Tam), or 17-β-estradiol (E<sub>2</sub>) after which cells were analyzed for proliferation rates and mRNA expression by RT-PCR. In our <it>in vivo </it>studies, MMTV-Neu mice were injected with β-HCH and observed for tumor formation over a 70 week period.</p> <p>Results</p> <p>β-HCH and Tam selected MCF10AT1 cells demonstrated increased mRNA expression of MMP-13 (collagenase-3) a marker of increased invasiveness. β-HCH treatment was also seen to increase the expression in a number of proto-oncogenes (c-Neu, Cyclin D1, p27), cell status markers (Met-1, CK19), and the inflammatory marker NFκB. Previous studies, have demonstrated the role of these markers as evidence of malignant transformations, and further illustrate the ability of β-HCH to be carcinogenic. To demonstrate β-HCH's tumorigenic properties in an <it>in vivo </it>system, we used an MMTV-Neu mouse model.</p> <p>MMTV-Neu is a c-Neu overexpressing strain which has been shown to spontaneously develop mammary tumors at later stages of aging. In this experiment, β-HCH exposure was shown to both accelerate the appearance (~8 weeks for median tumor-free period) and incidence (~25% increase at the end of the test period) of tumors when compared to control mice receiving only the corn-oil vehicle.</p> <p>Conclusion</p> <p>Based upon these results, it was concluded that β-HCH does act as a breast cancer promoter which exerts its tumorigenic activity via increased c-Neu expression.</p> |
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| institution | Directory Open Access Journal |
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| language | English |
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| spelling | doaj.art-0bc2192adf214f00a851e970154bd4022022-12-22T02:46:40ZengBMCBMC Cancer1471-24072007-07-017113010.1186/1471-2407-7-130Promotion of breast cancer by β-Hexachlorocyclohexane in MCF10AT1 cells and MMTV-neu miceMatsumura FumioWong Patrick S<p>Abstract</p> <p>Background</p> <p>Exposure to β-Hexachlorocyclohexane (β-HCH), a contaminant of the hexachlorohexane pesticide lindane, has been implicated as a risk factor in the development of breast cancers in epidemiological studies. Previous studies in our laboratory have demonstrated the ability of β-HCH to elicit its actions via a ligand-independent activation of the estrogen receptor through increased c-Neu (= erbB<sub>2 </sub>or HER-2) expression and kinase activation in both the BG-1 and MCF-7 cell lines. In addition, long term exposure (33 passages) to β-HCH was shown to promote the selection of MCF-7 cells which exhibit a more metastatic phenotype.</p> <p>Methods</p> <p>In this current study, we decided to investigate the long-term effects of β-HCH in both the MCF10AT1 cell line which was derived from a normal epithelial cell line by stably transfecting a mutated c-Ha-ras and a MMTV-Neu mouse model for mammary cancer <it>in vivo</it>. MCF10AT1 cells were exposed for 20 passages with β-HCH, 4-OH-Tamoxifen (Tam), or 17-β-estradiol (E<sub>2</sub>) after which cells were analyzed for proliferation rates and mRNA expression by RT-PCR. In our <it>in vivo </it>studies, MMTV-Neu mice were injected with β-HCH and observed for tumor formation over a 70 week period.</p> <p>Results</p> <p>β-HCH and Tam selected MCF10AT1 cells demonstrated increased mRNA expression of MMP-13 (collagenase-3) a marker of increased invasiveness. β-HCH treatment was also seen to increase the expression in a number of proto-oncogenes (c-Neu, Cyclin D1, p27), cell status markers (Met-1, CK19), and the inflammatory marker NFκB. Previous studies, have demonstrated the role of these markers as evidence of malignant transformations, and further illustrate the ability of β-HCH to be carcinogenic. To demonstrate β-HCH's tumorigenic properties in an <it>in vivo </it>system, we used an MMTV-Neu mouse model.</p> <p>MMTV-Neu is a c-Neu overexpressing strain which has been shown to spontaneously develop mammary tumors at later stages of aging. In this experiment, β-HCH exposure was shown to both accelerate the appearance (~8 weeks for median tumor-free period) and incidence (~25% increase at the end of the test period) of tumors when compared to control mice receiving only the corn-oil vehicle.</p> <p>Conclusion</p> <p>Based upon these results, it was concluded that β-HCH does act as a breast cancer promoter which exerts its tumorigenic activity via increased c-Neu expression.</p>http://www.biomedcentral.com/1471-2407/7/130 |
| spellingShingle | Matsumura Fumio Wong Patrick S Promotion of breast cancer by β-Hexachlorocyclohexane in MCF10AT1 cells and MMTV-neu mice BMC Cancer |
| title | Promotion of breast cancer by β-Hexachlorocyclohexane in MCF10AT1 cells and MMTV-neu mice |
| title_full | Promotion of breast cancer by β-Hexachlorocyclohexane in MCF10AT1 cells and MMTV-neu mice |
| title_fullStr | Promotion of breast cancer by β-Hexachlorocyclohexane in MCF10AT1 cells and MMTV-neu mice |
| title_full_unstemmed | Promotion of breast cancer by β-Hexachlorocyclohexane in MCF10AT1 cells and MMTV-neu mice |
| title_short | Promotion of breast cancer by β-Hexachlorocyclohexane in MCF10AT1 cells and MMTV-neu mice |
| title_sort | promotion of breast cancer by β hexachlorocyclohexane in mcf10at1 cells and mmtv neu mice |
| url | http://www.biomedcentral.com/1471-2407/7/130 |
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