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

Breast Cancer Res Treat. 2022 Nov;196(1):17-30. doi: 10.1007/s10549-022-06715-z. Epub 2022 Aug 27.


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.

Keywords: CDK; Cell cycle; Chemotherapy; Tamoxifen; Triple negative breast cancer.

MeSH terms

  • Animals
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / genetics
  • Breast Neoplasms* / metabolism
  • Cell Cycle
  • Cell Cycle Checkpoints
  • Cell Line, Tumor
  • Cell Proliferation
  • Cyclins
  • Female
  • Humans
  • Mice
  • RNA, Small Interfering
  • Tamoxifen / pharmacology
  • Triple Negative Breast Neoplasms* / drug therapy
  • Triple Negative Breast Neoplasms* / genetics
  • Triple Negative Breast Neoplasms* / metabolism


  • Cyclins
  • RNA, Small Interfering
  • Tamoxifen