miRNA-34b as a tumor suppressor in estrogen-dependent growth of breast cancer cells

Yee Ming Lee, Jen Yi Lee, Chao Chi Ho, Qi Sheng Hong, Sung Liang Yu, Chii Ruey Tzeng, Pan Chyr Yang, Huei Wen Chen

Research output: Contribution to journalArticle

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Abstract

Introduction: Estrogen is involved in several physiological and pathological processes through estrogen receptor (ER)-mediated transcriptional gene regulation. miRNAs (miRs), which are noncoding RNA genes, may respond to estrogen and serve as posttranscriptional regulators in tumorigenic progression, especially in breast cancer; however, only limited information about this possibility is available. In the present study, we identified the estrogen-regulated miR-34b and investigated its functional role in breast cancer progression.Methods: Estrogen-regulated miRNAs were identified by using a TaqMan low density array. Our in vivo Tet-On system orthotopic model revealed the tumor-suppressive ability of miR-34b. Luciferase reporter assays and chromatin immunoprecipitation assay demonstrated miR-34b were regulated by p53-ER interaction.Results: In this study, we identified one such estrogen downregulated miRNA, miR-34b, as an oncosuppressor that targets cyclin D1 and Jagged-1 (JAG1) in an ER+/wild-type p53 breast cancer cell line (MCF-7), as well as in ovarian and endometrial cells, but not in ER-negative or mutant p53 breast cancer cell lines (T47D, MBA-MB-361 and MDA-MB-435). There is a negative association between ERα and miR-34b expression levels in ER+ breast cancer patients. Tet-On induction of miR-34b can cause inhibition of tumor growth and cell proliferation. Also, the overexpression of miR-34b inhibited ER+ breast tumor growth in an orthotopic mammary fat pad xenograft mouse model. Further validation indicated that estrogen's inhibition of miR-34b expression was mediated by interactions between ERα and p53, not by DNA methylation regulation. The xenoestrogens diethylstilbestrol and zeranol also showed similar estrogenic effects by inhibiting miR-34b expression and by restoring the protein levels of the miR-34b targets cyclin D1 and JAG1 in MCF-7 cells.Conclusions: These findings reveal that miR-34b is an oncosuppressor miRNA requiring both ER+ and wild-type p53 phenotypes in breast cancer cells. These results improve our ability to develop new therapeutic strategies to target the complex estrogenic pathway in human breast cancer progression through miRNA regulation.

Original languageEnglish
Article numberR116
JournalBreast Cancer Research
Volume13
Issue number6
DOIs
Publication statusPublished - Nov 23 2011

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MicroRNAs
Estrogen Receptors
Estrogens
Breast Neoplasms
Growth
Neoplasms
Cyclin D1
Zeranol
Physiological Phenomena
Cell Line
Untranslated RNA
Diethylstilbestrol
Chromatin Immunoprecipitation
MCF-7 Cells
DNA Methylation
Pathologic Processes
Luciferases
Heterografts
Genes
Adipose Tissue

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Lee, Y. M., Lee, J. Y., Ho, C. C., Hong, Q. S., Yu, S. L., Tzeng, C. R., ... Chen, H. W. (2011). miRNA-34b as a tumor suppressor in estrogen-dependent growth of breast cancer cells. Breast Cancer Research, 13(6), [R116]. https://doi.org/10.1186/bcr3059

miRNA-34b as a tumor suppressor in estrogen-dependent growth of breast cancer cells. / Lee, Yee Ming; Lee, Jen Yi; Ho, Chao Chi; Hong, Qi Sheng; Yu, Sung Liang; Tzeng, Chii Ruey; Yang, Pan Chyr; Chen, Huei Wen.

In: Breast Cancer Research, Vol. 13, No. 6, R116, 23.11.2011.

Research output: Contribution to journalArticle

Lee, YM, Lee, JY, Ho, CC, Hong, QS, Yu, SL, Tzeng, CR, Yang, PC & Chen, HW 2011, 'miRNA-34b as a tumor suppressor in estrogen-dependent growth of breast cancer cells', Breast Cancer Research, vol. 13, no. 6, R116. https://doi.org/10.1186/bcr3059
Lee, Yee Ming ; Lee, Jen Yi ; Ho, Chao Chi ; Hong, Qi Sheng ; Yu, Sung Liang ; Tzeng, Chii Ruey ; Yang, Pan Chyr ; Chen, Huei Wen. / miRNA-34b as a tumor suppressor in estrogen-dependent growth of breast cancer cells. In: Breast Cancer Research. 2011 ; Vol. 13, No. 6.
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AU - Yu, Sung Liang

AU - Tzeng, Chii Ruey

AU - Yang, Pan Chyr

AU - Chen, Huei Wen

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N2 - Introduction: Estrogen is involved in several physiological and pathological processes through estrogen receptor (ER)-mediated transcriptional gene regulation. miRNAs (miRs), which are noncoding RNA genes, may respond to estrogen and serve as posttranscriptional regulators in tumorigenic progression, especially in breast cancer; however, only limited information about this possibility is available. In the present study, we identified the estrogen-regulated miR-34b and investigated its functional role in breast cancer progression.Methods: Estrogen-regulated miRNAs were identified by using a TaqMan low density array. Our in vivo Tet-On system orthotopic model revealed the tumor-suppressive ability of miR-34b. Luciferase reporter assays and chromatin immunoprecipitation assay demonstrated miR-34b were regulated by p53-ER interaction.Results: In this study, we identified one such estrogen downregulated miRNA, miR-34b, as an oncosuppressor that targets cyclin D1 and Jagged-1 (JAG1) in an ER+/wild-type p53 breast cancer cell line (MCF-7), as well as in ovarian and endometrial cells, but not in ER-negative or mutant p53 breast cancer cell lines (T47D, MBA-MB-361 and MDA-MB-435). There is a negative association between ERα and miR-34b expression levels in ER+ breast cancer patients. Tet-On induction of miR-34b can cause inhibition of tumor growth and cell proliferation. Also, the overexpression of miR-34b inhibited ER+ breast tumor growth in an orthotopic mammary fat pad xenograft mouse model. Further validation indicated that estrogen's inhibition of miR-34b expression was mediated by interactions between ERα and p53, not by DNA methylation regulation. The xenoestrogens diethylstilbestrol and zeranol also showed similar estrogenic effects by inhibiting miR-34b expression and by restoring the protein levels of the miR-34b targets cyclin D1 and JAG1 in MCF-7 cells.Conclusions: These findings reveal that miR-34b is an oncosuppressor miRNA requiring both ER+ and wild-type p53 phenotypes in breast cancer cells. These results improve our ability to develop new therapeutic strategies to target the complex estrogenic pathway in human breast cancer progression through miRNA regulation.

AB - Introduction: Estrogen is involved in several physiological and pathological processes through estrogen receptor (ER)-mediated transcriptional gene regulation. miRNAs (miRs), which are noncoding RNA genes, may respond to estrogen and serve as posttranscriptional regulators in tumorigenic progression, especially in breast cancer; however, only limited information about this possibility is available. In the present study, we identified the estrogen-regulated miR-34b and investigated its functional role in breast cancer progression.Methods: Estrogen-regulated miRNAs were identified by using a TaqMan low density array. Our in vivo Tet-On system orthotopic model revealed the tumor-suppressive ability of miR-34b. Luciferase reporter assays and chromatin immunoprecipitation assay demonstrated miR-34b were regulated by p53-ER interaction.Results: In this study, we identified one such estrogen downregulated miRNA, miR-34b, as an oncosuppressor that targets cyclin D1 and Jagged-1 (JAG1) in an ER+/wild-type p53 breast cancer cell line (MCF-7), as well as in ovarian and endometrial cells, but not in ER-negative or mutant p53 breast cancer cell lines (T47D, MBA-MB-361 and MDA-MB-435). There is a negative association between ERα and miR-34b expression levels in ER+ breast cancer patients. Tet-On induction of miR-34b can cause inhibition of tumor growth and cell proliferation. Also, the overexpression of miR-34b inhibited ER+ breast tumor growth in an orthotopic mammary fat pad xenograft mouse model. Further validation indicated that estrogen's inhibition of miR-34b expression was mediated by interactions between ERα and p53, not by DNA methylation regulation. The xenoestrogens diethylstilbestrol and zeranol also showed similar estrogenic effects by inhibiting miR-34b expression and by restoring the protein levels of the miR-34b targets cyclin D1 and JAG1 in MCF-7 cells.Conclusions: These findings reveal that miR-34b is an oncosuppressor miRNA requiring both ER+ and wild-type p53 phenotypes in breast cancer cells. These results improve our ability to develop new therapeutic strategies to target the complex estrogenic pathway in human breast cancer progression through miRNA regulation.

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