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PACT promotes the metastasis of basal-like breast cancer through Rac1 SUMOylation and activation

Abstract

Most basal-like breast cancers (BLBCs) are triple-negative breast cancers (TNBCs), which is associated with high malignancy, high rate of recurrence and distant metastasis, and poor prognosis among all types of breast cancer. However, there are currently no effective therapies for BLBC. Furthermore, chemoresistance limits the therapeutic options for BLBC treatment. In this study, we screen out protein activator of the interferon-induced protein kinase (PACT) as an essential gene in BLBC metastasis. We find that high PACT expression level was associated with poor prognosis among BLBC patients. In vivo and in vitro investigations indicated that PACT could regulate BLBC metastasis by interacting with SUMO-conjugating enzyme Ubc9 to stimulate the SUMOylation and thus consequently the activation of Rac1. BLBC patients receiving chemotherapy presents poorer prognosis with PACT high expression, and PACT disruption sensitizes experimental mammary tumor metastases to chemotherapy, thus providing insights to consider PACT as a potential therapeutic target to overcome acquired chemoresistance in BLBC.

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Fig. 1: PACT is screened as an upregulated protein in a BLBC metastasis model.
Fig. 2: PACT is correlated with poor prognosis and pathogenesis in breast cancer and is highly expressed specifically in BLBC.
Fig. 3: PACT promotes metastasis of BLBC cell.
Fig. 4: PACT activates Rac1 activity.
Fig. 5: PACT directly interacts with Ubc9 and regulates Rac1 SUMOylation.
Fig. 6: Rac1 SUMOylation is necessary for its activation by PACT.
Fig. 7: Inhibition of PACT enhances the therapeutic effect of chemotherapy on BLBC metastasis.

Data availability

RNA seq and RIP seq data generated for this publication have been deposited in NCBI’s SRA database under the accession: PRJNA643693

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Acknowledgements

This research was supported by the National Natural Science Foundation of China (31701217 to LW, and 31570921 to ZJK), Shanghai Key Laboratory of Health Identification and Assessment (13DZ2261000), Shanghai Municipal Commission of Health and Family Planning (201540206 to ZJK).

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ZJK and JL oversaw the study. ZJK and LW designed the research, outlined the manuscript, contributed to the literature search. ZJK, DW and XW contribute to manuscript editing. LW, WW, ZC and ZX contribute to data collection, and data analysis, provided the figures. LW drafted the manuscript, helped with data interpretation with additional input from all authors. JY collected clinical sample and did the staining.

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Correspondence to Zun-Ji Ke.

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All animal experiments were carried out with the approval of the institutional Animal Care and Use Committee at Shanghai University of Traditional Chinese Medicine. (Ethics license, PZSHUTCM191108010). The breast cancer specimens used in the current study were obtained from The Zhongshan Hospital of Fudan University, Qingpu branch with patient consent and institutional review board approval.

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Wei, L., Wang, W., Yao, J. et al. PACT promotes the metastasis of basal-like breast cancer through Rac1 SUMOylation and activation. Oncogene 41, 4282–4294 (2022). https://doi.org/10.1038/s41388-022-02431-6

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