Dissecting the Origin of Breast Cancer Subtype Stem Cell and the Potential Mechanism of Malignant Transformation

PLoS One. 2016 Oct 21;11(10):e0165001. doi: 10.1371/journal.pone.0165001. eCollection 2016.


Background: Breast cancer is the most common incident form of cancer in women including different subtypes. Cancer stem cells (CSCs) have been confirmed to exist in breast cancer. But the research on the origin of breast cancer subtype stem cells (BCSSCs) is still inadequate.

Methods: We identified the putative origin cells of BCSSCs through comparing gene signatures between BCSSCs and normal mammary cells from multiple perspectives: common signature, expression consistency, functional similarity and shortest path length. First, the potential origin cells were ranked according to these measures separately. Then Q statistic was employed to combine all rank lists into a unique list for each subtype, to prioritize the origin cells for each BCSSC. Next, we identified origin-related gene modules through integrating functional interaction network with differentially expressed genes. Finally, transcription factors of significant gene modules were predicted by MatchTM.

Results: The results showed that Luminal A CSC was most relevant to luminal progenitor cell or mature luminal cell; luminal B and HER2 CSC were most relevant to bipotent-enriched progenitor cell; basal-like CSC was most relevant to bipotent-enriched progenitor cell or mature luminal cell. Network modules analysis revealed genes related to mitochondrial respiratory chain (MRC) were significantly dysregulated during the origin of luminal B CSC. In addition, SOX10 emerged as a key regulator of MRC.

Conclusions: Our study supports substantive evidence for the possible origin of four kinds of BCSSCs. Dysfunction of MRC may contribute to the origin of luminal B CSC. These findings may have important implications to treat and prevent breast cancer.

MeSH terms

  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology*
  • Cell Transformation, Neoplastic*
  • Female
  • Gene Expression Profiling
  • Humans
  • Neoplastic Stem Cells / pathology*
  • Transcription, Genetic

Grants and funding

This work was supported by the Foundation for the National Natural Science Foundation of China [61571169] and the Natural Science Foundation of Heilongjiang Province of China [QC2014C017], and the University Nursing Program for Young Scholars with Creative Talents in Heilongjiang Province [UNPYSCT-2015037].