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Stabilization of c-Myc by the atypical cell cycle regulator, Spy1, decreases efficacy of breast cancer treatments

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Abstract

Purpose

c-Myc is frequently upregulated in breast cancers, however, targeting c-Myc has proven to be a challenge. Targeting of downstream mediators of c-Myc, such as the ‘cyclin-like’ cell cycle regulator Spy1, may be a viable therapeutic option in a subset of breast cancer subtypes.

Methods

Mouse mammary tumor cells isolated from MMTV-Myc mice and human breast cancer cell lines were used to manipulate Spy1 levels followed by tamoxifen or chemotherapeutic treatment with a variety of endpoints. Patient samples from TNBC patients were obtained and constructed into a TMA and stained for c-Myc and Spy1 protein levels.

Results

Over time, MMTV-Myc cells show a decreased response to tamoxifen treatment with increasing levels of Spy1 in the tamoxifen-resistant cells. shRNA against Spy1 re-establishes tamoxifen sensitivity. Spy1 was found to be highly elevated in human TNBC cell and patient samples, correlating to c-Myc protein levels. c-Myc was found to be stabilized by Spy1 and knocking down Spy1 in TNBC cells shows a significant increase in response to chemotherapy treatments.

Conclusion

Understanding the interplay between protein expression level and response to treatment is a critical factor in developing novel treatment options for breast cancer patients. These data have shown a connection between Spy1 and c-Myc protein levels in more aggressive breast cancer cells and patient samples. Furthermore, targeting c-Myc has proven difficult, these data suggest targeting Spy1 even when c-Myc is elevated can confer an advantage to current chemotherapies.

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Data availability

Enquiries about data availability should be directed to the authors.

Abbreviations

BL:

Basal-like

BSA:

Bovine serum albumin

CDK:

Cyclin dependent kinase

CHX:

Cyclohexamide

ERα:

Estrogen receptor alpha

Her2/neu:

Human epidermal growth factor receptor 2

IB:

Immunoblotting

IM:

Immunomodulatory

IHC:

Immunohistochemistry

LAR:

Luminal androgen receptor

M:

Mesenchymal

MMTV:

Mouse mammary tumor virus

MSL:

Mesenchymal stem-like

PBS:

Phosphate buffered saline

PR:

Progesterone receptor

Spy1:

Speedy

TMA:

Tissue microarray

TNBC:

Triple negative breast cancer

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Acknowledgements

We would like to thank the Windsor Regional Cancer Centre, pathology department, and Dr. D. Shum for the assistance in acquiring patient tumor samples. We acknowledge and thank the patients of the clinical trial. Biological Materials were provided by the Ontario Tumour Bank, which is funded by the Ontario Institute for Cancer Research.

Funding

R-MF and BF acknowledge scholarship support from the Canadian Breast Cancer Foundation. This work was supported by operating funds from the Canadian Institutes Health Research to L.A.P (Grant#142189).

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Author notes

  1. Rosa-Maria Ferraiuolo and Bre-Anne Fifield contributed equally to this work.

Authors and Affiliations

  1. Department of Biomedical Sciences, University of Windsor, Windsor, ON, N9B 3P4, Canada

    Rosa-Maria Ferraiuolo, Bre-Anne Fifield, Caroline Hamm & Lisa A. Porter

  2. Windsor Regional Cancer Centre, Windsor Regional Hospital, Windsor, ON, N9C 3E6, Canada

    Caroline Hamm

  3. Western University, Windsor, ON, N9B 3P4, Canada

    Caroline Hamm

  4. WE-SPARK Health Institute, Windsor, ON, N9B 3P4, Canada

    Bre-Anne Fifield, Caroline Hamm & Lisa A. Porter

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  1. Rosa-Maria Ferraiuolo
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  4. Lisa A. Porter
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Contributions

R-MF carried out all of the experiments described herein and aided in the draft of the manuscript. BF aided in the draft of the manuscript and in revisions to the manuscript and data analysis. CH is a valuable collaborator and the principal investigator in the clinic, acquiring patient consent and tissue for the trial. LAP funded the project and had a lead role in study design, interpretation of the data and manuscript preparation. All authors edited the manuscript and provided comments on the intellectual content.

Corresponding author

Correspondence to Lisa A. Porter.

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The authors declare they have no competing interests.

Ethical approval

Approval to receive samples from the Ontario Tumour Bank and Windsor Regional Hospital has been approved by the University of Windsor Research Ethics Board under REB #14-123.

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Ferraiuolo, RM., Fifield, BA., Hamm, C. et al. Stabilization of c-Myc by the atypical cell cycle regulator, Spy1, decreases efficacy of breast cancer treatments. Breast Cancer Res Treat 196, 17–30 (2022). https://doi.org/10.1007/s10549-022-06715-z

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