Targeting Pin1 by All-Trans Retinoic Acid (ATRA) Overcomes Tamoxifen Resistance in Breast Cancer via Multifactorial Mechanisms
Breast cancer is the most prevalent tumor in women worldwide and about 70% patients are estrogen receptor positive. In these cancer patients, resistance to the anticancer estrogen receptor antagonist tamoxifen emerges to be a major clinical obstacle. Peptidyl-prolyl isomerase Pin1 is prominently ove...
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| Format: | Article |
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Frontiers Media S.A.
2019-12-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fcell.2019.00322/full |
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| author | Songyin Huang Yang Chen Zhi-Mei Liang Zhi-Mei Liang Na-Na Li Na-Na Li Yujie Liu Yujie Liu Yinghua Zhu Yinghua Zhu Dingzhun Liao Xiao Zhen Zhou Kun Ping Lu Yandan Yao Yandan Yao Man-Li Luo Man-Li Luo |
| author_facet | Songyin Huang Yang Chen Zhi-Mei Liang Zhi-Mei Liang Na-Na Li Na-Na Li Yujie Liu Yujie Liu Yinghua Zhu Yinghua Zhu Dingzhun Liao Xiao Zhen Zhou Kun Ping Lu Yandan Yao Yandan Yao Man-Li Luo Man-Li Luo |
| author_sort | Songyin Huang |
| collection | DOAJ |
| description | Breast cancer is the most prevalent tumor in women worldwide and about 70% patients are estrogen receptor positive. In these cancer patients, resistance to the anticancer estrogen receptor antagonist tamoxifen emerges to be a major clinical obstacle. Peptidyl-prolyl isomerase Pin1 is prominently overexpressed in breast cancer and involves in tamoxifen-resistance. Here, we explore the mechanism and effect of targeting Pin1 using its chemical inhibitor all-trans retinoic acid (ATRA) in the treatment of tamoxifen-resistant breast cancer. We found that Pin1 was up-regulated in tamoxifen-resistant human breast cancer cell lines and tumor tissues from relapsed patients. Pin1 overexpression increased the phosphorylation of ERα on S118 and stabilized ERα protein. ATRA treatment, resembling the effect of Pin1 knockdown, promoted ERα degradation in tamoxifen-resistant cells. Moreover, ATRA or Pin1 knockdown decreased the activation of ERK1/2 and AKT pathways. ATRA also reduced the nuclear expression and transcriptional activity of ERα. Importantly, ATRA inhibited cell viability and proliferation of tamoxifen-resistant human breast cancer cells in vitro. Slow-releasing ATRA tablets reduced the growth of tamoxifen-resistant human breast cancer xenografts in vivo. In conclusion, ATRA-induced Pin1 ablation inhibits tamoxifen-resistant breast cancer growth by suppressing multifactorial mechanisms of tamoxifen resistance simultaneously, which demonstrates an attractive strategy for treating aggressive and endocrine-resistant tumors. |
| first_indexed | 2024-12-16T17:36:20Z |
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| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-16T17:36:20Z |
| publishDate | 2019-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-9f8bcec373754f78aa757c66bed16f152022-12-21T22:22:46ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2019-12-01710.3389/fcell.2019.00322499361Targeting Pin1 by All-Trans Retinoic Acid (ATRA) Overcomes Tamoxifen Resistance in Breast Cancer via Multifactorial MechanismsSongyin Huang0Yang Chen1Zhi-Mei Liang2Zhi-Mei Liang3Na-Na Li4Na-Na Li5Yujie Liu6Yujie Liu7Yinghua Zhu8Yinghua Zhu9Dingzhun Liao10Xiao Zhen Zhou11Kun Ping Lu12Yandan Yao13Yandan Yao14Man-Li Luo15Man-Li Luo16Department of Clinical Laboratory, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, ChinaDepartment of Clinical Laboratory, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, ChinaMedical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, ChinaMedical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, ChinaBreast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, ChinaMedical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, ChinaDepartment of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, ChinaDivision of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United StatesDivision of Translational Therapeutics, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United StatesGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, ChinaBreast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, ChinaMedical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, ChinaBreast cancer is the most prevalent tumor in women worldwide and about 70% patients are estrogen receptor positive. In these cancer patients, resistance to the anticancer estrogen receptor antagonist tamoxifen emerges to be a major clinical obstacle. Peptidyl-prolyl isomerase Pin1 is prominently overexpressed in breast cancer and involves in tamoxifen-resistance. Here, we explore the mechanism and effect of targeting Pin1 using its chemical inhibitor all-trans retinoic acid (ATRA) in the treatment of tamoxifen-resistant breast cancer. We found that Pin1 was up-regulated in tamoxifen-resistant human breast cancer cell lines and tumor tissues from relapsed patients. Pin1 overexpression increased the phosphorylation of ERα on S118 and stabilized ERα protein. ATRA treatment, resembling the effect of Pin1 knockdown, promoted ERα degradation in tamoxifen-resistant cells. Moreover, ATRA or Pin1 knockdown decreased the activation of ERK1/2 and AKT pathways. ATRA also reduced the nuclear expression and transcriptional activity of ERα. Importantly, ATRA inhibited cell viability and proliferation of tamoxifen-resistant human breast cancer cells in vitro. Slow-releasing ATRA tablets reduced the growth of tamoxifen-resistant human breast cancer xenografts in vivo. In conclusion, ATRA-induced Pin1 ablation inhibits tamoxifen-resistant breast cancer growth by suppressing multifactorial mechanisms of tamoxifen resistance simultaneously, which demonstrates an attractive strategy for treating aggressive and endocrine-resistant tumors.https://www.frontiersin.org/article/10.3389/fcell.2019.00322/fullATRAPin1breast cancertamoxifenERα |
| spellingShingle | Songyin Huang Yang Chen Zhi-Mei Liang Zhi-Mei Liang Na-Na Li Na-Na Li Yujie Liu Yujie Liu Yinghua Zhu Yinghua Zhu Dingzhun Liao Xiao Zhen Zhou Kun Ping Lu Yandan Yao Yandan Yao Man-Li Luo Man-Li Luo Targeting Pin1 by All-Trans Retinoic Acid (ATRA) Overcomes Tamoxifen Resistance in Breast Cancer via Multifactorial Mechanisms Frontiers in Cell and Developmental Biology ATRA Pin1 breast cancer tamoxifen ERα |
| title | Targeting Pin1 by All-Trans Retinoic Acid (ATRA) Overcomes Tamoxifen Resistance in Breast Cancer via Multifactorial Mechanisms |
| title_full | Targeting Pin1 by All-Trans Retinoic Acid (ATRA) Overcomes Tamoxifen Resistance in Breast Cancer via Multifactorial Mechanisms |
| title_fullStr | Targeting Pin1 by All-Trans Retinoic Acid (ATRA) Overcomes Tamoxifen Resistance in Breast Cancer via Multifactorial Mechanisms |
| title_full_unstemmed | Targeting Pin1 by All-Trans Retinoic Acid (ATRA) Overcomes Tamoxifen Resistance in Breast Cancer via Multifactorial Mechanisms |
| title_short | Targeting Pin1 by All-Trans Retinoic Acid (ATRA) Overcomes Tamoxifen Resistance in Breast Cancer via Multifactorial Mechanisms |
| title_sort | targeting pin1 by all trans retinoic acid atra overcomes tamoxifen resistance in breast cancer via multifactorial mechanisms |
| topic | ATRA Pin1 breast cancer tamoxifen ERα |
| url | https://www.frontiersin.org/article/10.3389/fcell.2019.00322/full |
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