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Endocrine resistant breast cancer cells with loss of ERα expression retain proliferative ability by reducing caspase7-mediated HDAC3 cleavage

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Abstract

Purpose

Endocrine therapy is the most commonly used approach for the treatment of estrogen receptor (ERα)-positive breast cancer. The cure rate of patients with ERα-positive breast cancer is, however, limited due to the occurrence of endocrine resistance. Loss of ERα is one major mechanism for the occurrence of endocrine resistance. Recent studies have shown that pan-HDAC inhibitors may be effective in reversing endocrine resistance. However, the molecular mechanism underlying this reversal has remained largely unknown. Here we aimed to unravel this mechanism.

Methods

Endocrine resistant breast cancer cell lines were established through exposure to tamoxifen. mRNA expression was assessed by qRT-PCR and protein expression by Western blotting. The effect of HDAC3 inhibition on the viability of endocrine resistant breast cancer cells was evaluated using CCK-8 and colony forming assays. Immunohistochemistry was used to detect protein expression in primary breast cancer tissues.

Results

We found that in endocrine resistant breast cancer cells loss of ERα led to HDAC3 stabilization via decreased ERα-mediated caspase7 expression, resulting in reduced caspase7-mediated HDAC3 cleavage. We also found that the ERα-caspase7-HDAC3 axis determined the global H3K9 and H4K16 acetylation status, which was positively correlated with ERα expression. Finally, we found that inhibition of HDAC3 significantly decreased the viability of endocrine resistant breast cancer cells exhibiting ERα deficiency. The ERα-caspase7-HDAC3 axis was subsequently verified in primary endocrine resistant breast cancer samples.

Conclusions

From our data we conclude that the ERα-caspase7-HDAC3 axis may play a role in promoting the proliferation of endocrine resistant breast cancer cells. HDAC3 may serve as a therapeutic target for (a subset of) endocrine resistant breast cancers exhibiting ERα loss.

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Acknowledgments

This work was funded by the National Natural Science Foundation of China (Grant No.: 81572712 & 81772956 to L. Chen), the National Basic Research Program of China (973 Program) (Grant No.: 2015CB965000 to L. Chen), the Key University Science Research Project of Jiangsu Province (Grant No.: 17KJA320002 to L. Chen), grants from the Natural Science Foundation of Jiangsu Province (Grant No.: SBK2016030027 to L. Chen), the Six talent peaks project in Jiangsu Province (Grant No.: 2015-JY-002 to L. Chen), a Jiangsu Shuangchuang talent program to L. Chen, and the Priority Academic Program Development of Jiangsu Higher Education Institutions. Science and Technology Program of Nanjing, China (Grant No.: 201803052 to Z. Yu).

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Author notes

  1. Shiyi Yu, Xue Gong and Zhifang Ma contributed equally to this work.

Authors and Affiliations

  1. Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, 210023, People’s Republic of China

    Shiyi Yu, Xue Gong, Zhifang Ma, Meng Zhang, Ling Huang, Jun Zhang & Liming Chen

  2. Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, People’s Republic of China

    Shuang Zhao & Zhenghong Yu

  3. Institute of Immunology and CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Biology, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, 230027, People’s Republic of China

    Tao Zhu

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  1. Shiyi Yu
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Contributions

Conception and design: Shiyi Yu, Tao Zhu, Zhenghong Yu, Liming Chen.

Development of methodology: Liming Chen, Zhenghong Yu.

Acquisition of data (provided animals, acquired and managed patients, provided facilities): Shiyi Yu, Xue Gong, Zhifang Ma, Meng Zhang, Ling Huang, Jun zhang, Shuang Zhao, Zhenghong Yu, Liming Chen.

Analysis and interpretation of data (i.e., statistical analysis, biostatistics, computational analysis): Liming Chen, Shiyi Yu, Zhifang Ma.

Writing, review and/or revision of the manuscript: Liming Chen, Shiyi Yu.

Administrative, technical or material support (i.e., reporting or organizing data, constructing databases): Tao Zhu, Shuang Zhao, Zhenghong Yu.

Study supervision: Liming Chen.

Other (approved final version): Liming Chen.

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Correspondence to Zhenghong Yu.

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Yu, S., Gong, X., Ma, Z. et al. Endocrine resistant breast cancer cells with loss of ERα expression retain proliferative ability by reducing caspase7-mediated HDAC3 cleavage. Cell Oncol. 43, 65–80 (2020). https://doi.org/10.1007/s13402-019-00439-x

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