Does inter-individual heterogeneity in the normal breast corrupt cancer stem cell and/or cancer-specific signaling characterization?

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

Several studies have described cell surface markers that phenotypically define stem-progenitor-mature cell hierarchy in the normal breast. The same markers have been used to identify subpopulation of cancer cells with enhanced tumor initiating capacity. These subpopulations of cells, also called cancer stem cells (CSCs), have been the focus of intense research for the last few years. Identifying and characterizing cancer-specific differences in CSCs from their normal counter part is not trivial due to non-availability of replenishable source of primary normal and CSCs to perform functional assays. Moreover, recent discovery of widespread genetic variation in humans leading to functional transcriptome diversity makes the task of defining "global normal" very difficult. Thus, "normal" breast epithelial hierarchy and corresponding gene expression profiles have to be defined at individual patient level for comparison with cancer. Recent advances in human mammary epithelial cell reprogramming growth conditions and single cell genome analyses should overcome these limitations and enable characterization of "normal" and "tumor" at individual levels. By propagating cells from core breast biopsies of healthy donors, tumors and adjacent normal followed by flow cytometry analysis, we have recently observed remarkable inter-individual phenotypic heterogeneity in normal breast stem, luminal progenitor, and mature cell numbers and possibly epithelial cell plasticity. Comparison of adjacent normal and tumor from the same patient showed distinct differences in differentiation status between normal and tumor. This observation has important implications as cancer-specific defect in differentiation alone could account for the majority of gene expression differences observed between cancer and normal cells. In addition, most of the differentially expressed genes including genes with highest expression difference, which are often considered for functional studies or as biomarkers of cancer cell behavior, are not causally linked to cancer. Collectively, inter-individual heterogeneity in the normal breast, the differences in the differentiation status between normal and tumor of the same patient, and differences in epithelial cellularity between normal and tumors used for gene expression studies may be the reasons for discrepancy in the literature with respect to gene expression based prognostic signatures, cancer-specific signaling pathway alterations, and CSC characterization. As a way forward, we propose that the magnitude of tumor heterogeneity and CSC phenotype is the product of individual's epithelial cell plasticity and cancer-specific mutation. In addition, we need to characterize normal and tumor on an individual basis for clear understanding of pathobiology of tumors.

Original languageEnglish (US)
Title of host publicationThe Stem Cell Microenvironment and Its Role in Regenerative Medicine and Cancer Pathogenesis
PublisherRiver Publishers
Pages35-44
Number of pages10
ISBN (Electronic)9788793519008
ISBN (Print)9788793379930
StatePublished - Feb 1 2017

Keywords

  • Breast cancer
  • Cancer stem cells
  • Epithelial hierarchy
  • Heterogeneity
  • Normal breast

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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  • Cite this

    Nakshatri, H. (2017). Does inter-individual heterogeneity in the normal breast corrupt cancer stem cell and/or cancer-specific signaling characterization? In The Stem Cell Microenvironment and Its Role in Regenerative Medicine and Cancer Pathogenesis (pp. 35-44). River Publishers.