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Low-molecular-weight cyclin E deregulates DNA replication and damage repair to promote genomic instability in breast cancer

Oncogene volume 41, pages 5331–5346 (2022)Cite this article

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Abstract

Low-molecular-weight cyclin E (LMW-E) is an N-terminus deleted (40 amino acid) form of cyclin E detected in breast cancer, but not in normal cells or tissues. LMW-E overexpression predicts poor survival in breast cancer patients independent of tumor proliferation rate, but the oncogenic mechanism of LMW-E and its unique function(s) independent of full-length cyclin E (FL-cycE) remain unclear. In the current study, we found LMW-E was associated with genomic instability in early-stage breast tumors (n = 725) and promoted genomic instability in human mammary epithelial cells (hMECs). Mechanistically, FL-cycE overexpression inhibited the proliferation of hMECs by replication stress and DNA damage accumulation, but LMW-E facilitated replication stress tolerance by upregulating DNA replication and damage repair. Specifically, LMW-E interacted with chromatin and upregulated the loading of minichromosome maintenance complex proteins (MCMs) in a CDC6 dependent manner and promoted DNA repair in a RAD51- and C17orf53-dependent manner. Targeting the ATR-CHK1-RAD51 pathway with ATR inhibitor (ceralasertib), CHK1 inhibitor (rabusertib), or RAD51 inhibitor (B02) significantly decreased the viability of LMW-E–overexpressing hMECs and breast cancer cells. Collectively, our findings delineate a novel role for LMW-E in tumorigenesis mediated by replication stress tolerance and genomic instability, providing novel therapeutic strategies for LMW-E–overexpressing breast cancers.

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Fig. 1: Low-molecular-weight cyclin E (LMW-E) independently predicts genomic instability in breast cancer patients.
Fig. 2: Low-molecular-weight cyclin E (LMW-E) causes genomic instability in human mammary epithelial cells (hMECs).
Fig. 3: Low-molecular-weight cyclin E (LMW-E) facilitates replication stress tolerance.
Fig. 4: Low-molecular-weight cyclin E (LMW-E) deregulates DNA replication and DNA damage pathways.
Fig. 5: Low-molecular-weight cyclin E (LMW-E) promotes the pre-replication complex assembly.
Fig. 6: Low-molecular-weight cyclin E (LMW-E) facilitates DNA damage repair.
Fig. 7: Low-molecular-weight cyclin E (LMW-E) increased sensitivity to drugs targeting the ATR-CHK1-RAD51 pathway.

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Data availability

The RNA-seq data have been deposited in the NCBI Sequence Read Archive (accession code PRJNA885484). Resources and reagents used in the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Erica Goodoff, Senior Scientific Editor in the Research Medical Library at The University of Texas MD Anderson Cancer Center, for editing this article.

Funding

Research reported in this manuscript was supported by Cancer Prevention Research Institute of Texas - Multi-Investigator Research Award (CPRIT-MIRA # RP180712) to KK and KKH, by the National Cancer Institute (NCI) R01CA223772 and R01CA255960 to KK, CPRIT Research Training Program grant RP170067 and RP210028 to ML and by the NCI through MD Anderson’s Cancer Center Support Grant (P30CA016672).

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Authors and Affiliations

  1. The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA

    Mi Li & Khandan Keyomarsi

  2. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Mi Li, Tuyen Bui, Tuyen Duong Thanh Nguyen, Linjie Luo & Khandan Keyomarsi

  3. Department of Medicine, Baylor College of Medicine, Houston, TX, USA

    Spiridon Tsavachidis

  4. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Fuchenchu Wang

  5. Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Asha S. Multani

  6. Department of Epidemiology and Population Health, Stanford University, Stanford, CA, USA

    Melissa L. Bondy

  7. Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Kelly K. Hunt

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Contributions

Conceptualization: ML and KK; Methodology: ML, TB, and ASM; Biostatistical analysis: ST and FW; Resources: MLB, KKH, and KK; interpreting the results: ML, ST, FW, TB, TDTN, LL, ASM, MLB, KKH, and KK; Writing—original draft preparation: ML, TDTN, LL, and KK; Writing—review and editing: ML, ST, FW, TB, TDTN, LL, ASM, MLB, KKH, and KK; Supervision: KK; Funding acquisition: KKH and KK. All authors have read and agreed to the submitted version of the manuscript.

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Correspondence to Khandan Keyomarsi.

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KKH declares – Armada Health medical advisory board; research funding to MD Anderson Cancer Center from Cairn Surgical, Eli Lilly & Co., and Lumicell.

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Li, M., Tsavachidis, S., Wang, F. et al. Low-molecular-weight cyclin E deregulates DNA replication and damage repair to promote genomic instability in breast cancer. Oncogene 41, 5331–5346 (2022). https://doi.org/10.1038/s41388-022-02527-z

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