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The Role of Mitotic Slippage in Creating a "Female Pregnancy-like System" in a Single Polyploid Giant Cancer Cell

Kristine Salmina1, Ninel Miriam Vainshelbaum1,2, Madara Kreishmane1

  • 1Cancer Research Division, Latvian Biomedical Research and Study Centre, LV-1067 Riga, Latvia.

International Journal of Molecular Sciences
|February 25, 2023
PubMed

Insights

Triple-negative breast cancer cells resist doxorubicin via mitotic slippage, forming distinct polyploid giant cell populations. One population buds offspring, while the other persists, suggesting a novel "maternal cancer germ cell" role in treatment recovery.

Area of Science:

  • Oncology
  • Cell Biology
  • Reproductive Biology

Background:

  • Triple-negative breast cancer (TNBC) cells, like MDA-MB-231, exhibit resistance to genotoxic agents such as doxorubicin (DOX).
  • This resistance is partly mediated by "mitotic slippage" (MS), a process where cells discard damaged DNA and avoid apoptosis.
  • Two distinct populations of polyploid giant cells (PGGCs) arise from MS, but their roles in treatment recovery are unclear.

Purpose of the Study:

  • To characterize the origin and relationship between two PGGC sub-populations arising from MS in TNBC cells.
  • To elucidate the role of MS and PGGCs in cellular response and recovery from doxorubicin treatment.
  • To investigate the potential "soma-germ transition" and "female pregnancy-like" mechanisms within PGGCs.

Main Methods:

  • Cell culture of MDA-MB-231 triple-negative breast cancer cells.
  • Treatment with doxorubicin (DOX) to induce mitotic slippage (MS).
  • In silico analysis to identify links between immune response and reproductive gene modules.
  • Microscopy and molecular markers (YAP1, OCT4A, MOS, EMI2, CDC42, ACTIN, TUBULIN) to characterize PGGC sub-populations and nuclear dynamics.

Main Results:

  • MS in TNBC cells leads to two PGGC sub-populations: budding cells releasing offspring and persistent cells with increased ploidy.
  • A "soma-germ transition" occurs during MS, forming a "maternal germ cell" characterized by specific nuclear markers (YAP1/OCT4A/MOS/EMI2).
  • In silico analysis revealed connections between innate immune response to cytosolic DNA and female pregnancy/placenta development genes in PGGCs.
  • Asymmetrical subnuclei were observed: one repairing DNA and budding, the other persisting and degrading DNA.
  • The proto-oncogene parathyroid-hormone-like-hormone may parthenogenetically stimulate the "maternal cancer germ cell", creating a "female pregnancy-like" system.

Conclusions:

  • Mitotic slippage in TNBC cells generates distinct PGGCs with potentially divergent roles in treatment resistance and recovery.
  • "Maternal cancer germ cells" undergoing MS may hijack pregnancy-related pathways, including hormonal signaling, to survive and proliferate.
  • This study reveals a novel mechanism of cancer cell adaptation and potential therapeutic resistance involving cell cycle, DNA repair, and reproductive biology parallels.
Keywords:
buddingcancerfemale pregnancy systeminnate immune responsematernal germ cellmitotic slippageparthenogenesisplacental developmental genespolyploid giant cellresistance to treatmentsoma-germ transition

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