Normal cell phenotypes of breast epithelial cells provide the foundation of a breast cancer taxonomy

Abstract

The current classification system for breast cancer is based on expression of empirical prognostic and predictive biomarkers. As an alternative, we propose a hypothesis-based ontological breast cancer classification modeled after the taxonomy of species in evolutionary biology. This approach uses normal breast epithelial cell types and differentiation lineages as the gold standard to classify tumors. We show that there are at least eleven previously undefined normal cell types in human breast epithelium and that each breast carcinoma is related to one of these normal cell types. We find that triple negative breast cancers do not have a ‘basal-like’ phenotype. Normal breast epithelial cells conform to four novel hormonal differentiation states and almost all human breast tumors duplicate one of these hormonal differentiation states which have significant survival differences. This ontological classification scheme provides actionable treatment strategies and provides an alternative approach for understanding tumor biology with wide-ranging implications for tumor taxonomy.

Keywords::

• biomarkers
• breast cancer diagnostics
• heterogeneity
• Nurses’ Health Study
• -omics
• pathology

Financial & competing interests disclosure

The authors acknowledge funding support from Breast Cancer Research Foundation, Play for P.I.N.K., NCI grant R01-CA146445-01, NIH Roadmap Epigenomics Project (to TA Ince) and NIH grant K08NS064168 (to S Santagata). TA Ince discloses related patent filing under review. T Ince was a scientific advisor to 30M Inc. (2007–2012). S Santagata was cofounder of and scientific advisor to Bayesian Diagnostics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

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