Accurate classification is essential for understanding the pathophysiology of a
disease and can inform therapeutic choices. For hematopoietic malignancies, a
classification scheme based on the phenotypic similarity between tumor cells and
normal cells has been successfully used to define tumor subtypes; however, use of
normal cell types as a reference by which to classify solid tumors has not been
widely emulated, in part due to more limited understanding of epithelial cell
differentiation compared with hematopoiesis. To provide a better definition of the
subtypes of epithelial cells comprising the breast epithelium, we performed a
systematic analysis of a large set of breast epithelial markers in more than 15,000
normal breast cells, which identified 11 differentiation states for normal luminal
cells. We then applied information from this analysis to classify human breast tumors
based on normal cell types into 4 major subtypes, HR0–HR3, which were
differentiated by vitamin D, androgen, and estrogen hormone receptor (HR) expression.
Examination of 3,157 human breast tumors revealed that these HR subtypes were
distinct from the current classification scheme, which is based on estrogen receptor,
progesterone receptor, and human epidermal growth factor receptor 2. Patient outcomes
were best when tumors expressed all 3 hormone receptors (subtype HR3) and worst when
they expressed none of the receptors (subtype HR0). Together, these data provide an
ontological classification scheme associated with patient survival differences and
provides actionable insights for treating breast tumors.
Sandro Santagata, Ankita Thakkar, Ayse Ergonul, Bin Wang, Terri Woo, Rong Hu, J. Chuck Harrell, George McNamara, Matthew Schwede, Aedin C. Culhane, David Kindelberger, Scott Rodig, Andrea Richardson, Stuart J. Schnitt, Rulla M. Tamimi, Tan A. Ince
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