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Tafazzin mediates tamoxifen resistance by regulating cellular phospholipid composition in ER-positive breast cancer

Cancer Gene Therapy volume 31, pages 69–81 (2024)Cite this article

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Abstract

Tamoxifen is the frontline therapeutic agent for the estrogen receptor-positive (ER + ) subtype of breast cancer patients, which accounts for 70–80% of total breast cancer incidents. However, clinical resistance to tamoxifen has become increasingly common, highlighting the need to identify the underlying cellular mechanisms. In our study, we employed a genome-scale CRISPR-Cas9 loss-of-function screen and validation experiments to discover that Tafazzin (TAZ), a mitochondrial transacylase, is crucial for maintaining the cellular sensitivity of ER+ breast cancer cells to tamoxifen and other chemotherapies. Mechanistically, we found that cardiolipin, whose synthesis and maturation rely on TAZ, is required to maintain cellular sensitivity to tamoxifen. Loss of metabolic enzymatic activity of TAZ causes ERα downregulation and therapy resistance. Interestingly, we observed that TAZ deficiency also led to the upregulation of lysophosphatidylcholine (LPC), which in turn suppressed ERα expression and nuclear localization, thereby contributing to tamoxifen resistance. LPC is further metabolized to lysophosphatidic acid (LPA), a bioactive molecule that supports cell survival. Thus, our findings suggest that the depletion of TAZ promotes tamoxifen resistance through an LPC-LPA phospholipid synthesis axis, and targeting this lipid metabolic pathway could restore cell susceptibility to tamoxifen treatment.

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Fig. 1: Genome-wide screen for tamoxifen resistance genes in ER-positive breast cancer cells.
Fig. 2: Depletion-of-TAZ induces multiple drug resistance in ER-positive breast cancer.
Fig. 3: Loss-of-TAZ down-regulates ERα signaling and reduces cell proliferation rate.
Fig. 4: Metabolic enzymatic activity of TAZ is essential for its role in tamoxifen resistance.
Fig. 5: TAZ KO alters cellular phospholipid metabolism and induces tamoxifen resistance.
Fig. 6: Blockade of the LPA synthesis and signaling pathway re-sensitizes tumor cells to tamoxifen treatment.

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Acknowledgements

We thank D. Pan for helping with MAGeCK analysis; Z. Chang and Q. Ye for generously sharing the tamoxifen resistance cell; We thank all members of the Zheng laboratory for helpful discussions and technical assistance. We thank the Technology Center for Protein Sciences at Tsinghua University for mass-spectrometry support, the Laboratory Animal Research Center for animal research support, and the Center of Biomedical Analysis at Tsinghua University for FACS and optical imaging support.

Funding

The study was partially supported by the National Key Research and Development Program of China (2020YFA0509400 to HZ), the National Science Foundation of China (81772981 and 81972462 to HZ), the Tsinghua University Initiative Scientific Research Program, and the Tsinghua-Peking Center for Life Sciences.

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Authors and Affiliations

  1. State Key Laboratory of Molecular Oncology and Department of Basic Medical Sciences, School of Medicine, Tsinghua University, 100084, Beijing, China

    Xuan Li, Luyang Zhao, Christopher G. Lin, Haitian Hu & Hanqiu Zheng

  2. Tsinghua-Peking Center for Life Sciences, Beijing, China

    Xuan Li

  3. Department of Basic Medical Sciences, School of Medicine, Tsinghua University, 100084, Beijing, China

    Yuan Zhang & Tengjiang Zhang

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  1. Xuan Li
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Contributions

XL and HZ designed the overall study. XL performed the experiments, analyzed data, and wrote the paper. TZ provided technical help for next-generation data analysis. LZ provided help with the CRISPR/Cas9 screening. YZ provided technical help for animal work. HH provided technical help for cell works. HZ supervised the overall study. HZ, CL, and XL revised the paper.

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Correspondence to Hanqiu Zheng.

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All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of Tsinghua University.

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Li, X., Zhang, Y., Zhang, T. et al. Tafazzin mediates tamoxifen resistance by regulating cellular phospholipid composition in ER-positive breast cancer. Cancer Gene Ther 31, 69–81 (2024). https://doi.org/10.1038/s41417-023-00683-2

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