HDAC2 and HDAC5 up-regulations modulate survivin and miR-125a-5p expressions and promote hormone therapy resistance in estrogen receptor positive breast cancer cells

Wen Tsung Huang, Yu Hsuan Tsai, Shang Hung Chen, Ching Wen Kuo, Yao-Lung Kuo, Kuo-Ting Lee, Wen Chung Chen, Pei Chih Wu, Chun Yu Chuang, Siao Muk Cheng, Chun Hui Lin, Euphemia Yee Leung, Yung Chieh Chang, Chun-Hei Cheung

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Intrinsic or acquired resistance to hormone therapy is frequently reported in estrogen receptor positive (ER + ) breast cancer patients. Even though dysregulations of histone deacetylases (HDACs) are known to promote cancer cells survival, the role of different HDACs in the induction of hormone therapy resistance in ER + breast cancer remains unclear. Survivin is a well-known pro-tumor survival molecule and miR-125a-5p is a recently discovered tumor suppressor. In this study, we found that ER + , hormone-independent, tamoxifen-resistant MCF7-TamC3 cells exhibit increased expression of HDAC2, HDAC5, and survivin, but show decreased expression of miR-125a-5p, as compared to the parental tamoxifen-sensitive MCF7 breast cancer cells. Molecular down-regulations of HDAC2, HDAC5, and survivin, and ectopic over-expression of miR-125a-5p, increased the sensitivity of MCF7-TamC3 cells to estrogen deprivation and restored the sensitivity to tamoxifen. The same treatments also further increased the sensitivity to estrogen-deprivation in the ER + hormone-dependent ZR-75-1 breast cancer cells in vitro. Kaplan-Meier analysis and receiver operating characteristic curve analysis of expression cohorts of breast tumor showed that high HDAC2 and survivin, and low miR-125a-5p, expression levels correlate with poor relapse-free survival in endocrine therapy and tamoxifen-treated ER + breast cancer patients. Further molecular analysis revealed that HDAC2 and HDAC5 positively modulates the expression of survivin, and negatively regulates the expression miR-125a-5p, in ER + MCF7, MCF7-TamC3, and ZR-75-1 breast cancer cells. These findings indicate that dysregulations of HDAC2 and HDAC5 promote the development of hormone independency and tamoxifen resistance in ERC breast cancer cells in part through expression regulation of survivin and miR-125a-5p.

Original languageEnglish
Article number902
JournalFrontiers in Pharmacology
Volume8
Issue numberDEC
DOIs
Publication statusPublished - 2017 Dec 13

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Estrogen Receptors
Up-Regulation
Hormones
Breast Neoplasms
Tamoxifen
Histone Deacetylases
MCF-7 Cells
Therapeutics
Estrogens
Neoplasms
Survival
Kaplan-Meier Estimate
ROC Curve
Cell Survival
Cohort Studies
Down-Regulation
Recurrence

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

Huang, Wen Tsung ; Tsai, Yu Hsuan ; Chen, Shang Hung ; Kuo, Ching Wen ; Kuo, Yao-Lung ; Lee, Kuo-Ting ; Chen, Wen Chung ; Wu, Pei Chih ; Chuang, Chun Yu ; Cheng, Siao Muk ; Lin, Chun Hui ; Leung, Euphemia Yee ; Chang, Yung Chieh ; Cheung, Chun-Hei. / HDAC2 and HDAC5 up-regulations modulate survivin and miR-125a-5p expressions and promote hormone therapy resistance in estrogen receptor positive breast cancer cells. In: Frontiers in Pharmacology. 2017 ; Vol. 8, No. DEC.
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abstract = "Intrinsic or acquired resistance to hormone therapy is frequently reported in estrogen receptor positive (ER + ) breast cancer patients. Even though dysregulations of histone deacetylases (HDACs) are known to promote cancer cells survival, the role of different HDACs in the induction of hormone therapy resistance in ER + breast cancer remains unclear. Survivin is a well-known pro-tumor survival molecule and miR-125a-5p is a recently discovered tumor suppressor. In this study, we found that ER + , hormone-independent, tamoxifen-resistant MCF7-TamC3 cells exhibit increased expression of HDAC2, HDAC5, and survivin, but show decreased expression of miR-125a-5p, as compared to the parental tamoxifen-sensitive MCF7 breast cancer cells. Molecular down-regulations of HDAC2, HDAC5, and survivin, and ectopic over-expression of miR-125a-5p, increased the sensitivity of MCF7-TamC3 cells to estrogen deprivation and restored the sensitivity to tamoxifen. The same treatments also further increased the sensitivity to estrogen-deprivation in the ER + hormone-dependent ZR-75-1 breast cancer cells in vitro. Kaplan-Meier analysis and receiver operating characteristic curve analysis of expression cohorts of breast tumor showed that high HDAC2 and survivin, and low miR-125a-5p, expression levels correlate with poor relapse-free survival in endocrine therapy and tamoxifen-treated ER + breast cancer patients. Further molecular analysis revealed that HDAC2 and HDAC5 positively modulates the expression of survivin, and negatively regulates the expression miR-125a-5p, in ER + MCF7, MCF7-TamC3, and ZR-75-1 breast cancer cells. These findings indicate that dysregulations of HDAC2 and HDAC5 promote the development of hormone independency and tamoxifen resistance in ERC breast cancer cells in part through expression regulation of survivin and miR-125a-5p.",
author = "Huang, {Wen Tsung} and Tsai, {Yu Hsuan} and Chen, {Shang Hung} and Kuo, {Ching Wen} and Yao-Lung Kuo and Kuo-Ting Lee and Chen, {Wen Chung} and Wu, {Pei Chih} and Chuang, {Chun Yu} and Cheng, {Siao Muk} and Lin, {Chun Hui} and Leung, {Euphemia Yee} and Chang, {Yung Chieh} and Chun-Hei Cheung",
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HDAC2 and HDAC5 up-regulations modulate survivin and miR-125a-5p expressions and promote hormone therapy resistance in estrogen receptor positive breast cancer cells. / Huang, Wen Tsung; Tsai, Yu Hsuan; Chen, Shang Hung; Kuo, Ching Wen; Kuo, Yao-Lung; Lee, Kuo-Ting; Chen, Wen Chung; Wu, Pei Chih; Chuang, Chun Yu; Cheng, Siao Muk; Lin, Chun Hui; Leung, Euphemia Yee; Chang, Yung Chieh; Cheung, Chun-Hei.

In: Frontiers in Pharmacology, Vol. 8, No. DEC, 902, 13.12.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - HDAC2 and HDAC5 up-regulations modulate survivin and miR-125a-5p expressions and promote hormone therapy resistance in estrogen receptor positive breast cancer cells

AU - Huang, Wen Tsung

AU - Tsai, Yu Hsuan

AU - Chen, Shang Hung

AU - Kuo, Ching Wen

AU - Kuo, Yao-Lung

AU - Lee, Kuo-Ting

AU - Chen, Wen Chung

AU - Wu, Pei Chih

AU - Chuang, Chun Yu

AU - Cheng, Siao Muk

AU - Lin, Chun Hui

AU - Leung, Euphemia Yee

AU - Chang, Yung Chieh

AU - Cheung, Chun-Hei

PY - 2017/12/13

Y1 - 2017/12/13

N2 - Intrinsic or acquired resistance to hormone therapy is frequently reported in estrogen receptor positive (ER + ) breast cancer patients. Even though dysregulations of histone deacetylases (HDACs) are known to promote cancer cells survival, the role of different HDACs in the induction of hormone therapy resistance in ER + breast cancer remains unclear. Survivin is a well-known pro-tumor survival molecule and miR-125a-5p is a recently discovered tumor suppressor. In this study, we found that ER + , hormone-independent, tamoxifen-resistant MCF7-TamC3 cells exhibit increased expression of HDAC2, HDAC5, and survivin, but show decreased expression of miR-125a-5p, as compared to the parental tamoxifen-sensitive MCF7 breast cancer cells. Molecular down-regulations of HDAC2, HDAC5, and survivin, and ectopic over-expression of miR-125a-5p, increased the sensitivity of MCF7-TamC3 cells to estrogen deprivation and restored the sensitivity to tamoxifen. The same treatments also further increased the sensitivity to estrogen-deprivation in the ER + hormone-dependent ZR-75-1 breast cancer cells in vitro. Kaplan-Meier analysis and receiver operating characteristic curve analysis of expression cohorts of breast tumor showed that high HDAC2 and survivin, and low miR-125a-5p, expression levels correlate with poor relapse-free survival in endocrine therapy and tamoxifen-treated ER + breast cancer patients. Further molecular analysis revealed that HDAC2 and HDAC5 positively modulates the expression of survivin, and negatively regulates the expression miR-125a-5p, in ER + MCF7, MCF7-TamC3, and ZR-75-1 breast cancer cells. These findings indicate that dysregulations of HDAC2 and HDAC5 promote the development of hormone independency and tamoxifen resistance in ERC breast cancer cells in part through expression regulation of survivin and miR-125a-5p.

AB - Intrinsic or acquired resistance to hormone therapy is frequently reported in estrogen receptor positive (ER + ) breast cancer patients. Even though dysregulations of histone deacetylases (HDACs) are known to promote cancer cells survival, the role of different HDACs in the induction of hormone therapy resistance in ER + breast cancer remains unclear. Survivin is a well-known pro-tumor survival molecule and miR-125a-5p is a recently discovered tumor suppressor. In this study, we found that ER + , hormone-independent, tamoxifen-resistant MCF7-TamC3 cells exhibit increased expression of HDAC2, HDAC5, and survivin, but show decreased expression of miR-125a-5p, as compared to the parental tamoxifen-sensitive MCF7 breast cancer cells. Molecular down-regulations of HDAC2, HDAC5, and survivin, and ectopic over-expression of miR-125a-5p, increased the sensitivity of MCF7-TamC3 cells to estrogen deprivation and restored the sensitivity to tamoxifen. The same treatments also further increased the sensitivity to estrogen-deprivation in the ER + hormone-dependent ZR-75-1 breast cancer cells in vitro. Kaplan-Meier analysis and receiver operating characteristic curve analysis of expression cohorts of breast tumor showed that high HDAC2 and survivin, and low miR-125a-5p, expression levels correlate with poor relapse-free survival in endocrine therapy and tamoxifen-treated ER + breast cancer patients. Further molecular analysis revealed that HDAC2 and HDAC5 positively modulates the expression of survivin, and negatively regulates the expression miR-125a-5p, in ER + MCF7, MCF7-TamC3, and ZR-75-1 breast cancer cells. These findings indicate that dysregulations of HDAC2 and HDAC5 promote the development of hormone independency and tamoxifen resistance in ERC breast cancer cells in part through expression regulation of survivin and miR-125a-5p.

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