Microenvironmental networks promote tumor heterogeneity and enrich for metastatic cancer stem-like cells in Luminal-A breast tumor cells

Oncotarget. 2016 Dec 6;7(49):81123-81143. doi: 10.18632/oncotarget.13213.


The roles of the tumor microenvironment (TME) in generating intra-tumoral diversity within each specific breast cancer subtype are far from being fully elucidated. In this study, we exposed Luminal-A breast cancer cells in culture to combined "TME Stimulation", representing three typical arms of the breast TME: hormonal (estrogen), inflammatory (tumor necrosis factor α) and growth-promoting (epidermal growth factor). In addition to enriching the tumor cell population with CD44+/β1+ cells (as we previously published), TME Stimulation selected for CD44+/CD24low/- stem-like cells, that were further enriched by doxorubicin treatment and demonstrated high plasticity in vitro and in vivo. Knock-down experiments revealed that CD44 and Zeb1 regulated CD24 and β1 expression and controlled differently cell spreading and formation of cellular protrusions. TME-enriched CD44+/CD24low/- stem-like cells promoted dissemination to bones and lymph nodes, whereas CD44+/β1+ cells had a low metastatic potential. Mixed co-injections of TME-enriched CD44+/CD24low/- and CD44+/β1+ sub-populations generated metastases populated mostly by CD44+/CD24low/--derived cells. Thus, combined activities of several TME factors select for CD44+/CD24low/- stem-like cells that dictate the metastatic phenotype of Luminal-A breast tumor cells, suggesting that therapeutic modalities targeting the TME could be introduced as a potential strategy of inhibiting the detrimental stem-like sub-population in this disease subtype.

Keywords: adhesion molecules; cancer stem cells; luminal-A breast cancer; metastasis; tumor microenvironment.

MeSH terms

  • Animals
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • CD24 Antigen / metabolism
  • Cell Movement* / drug effects
  • Cell Plasticity* / drug effects
  • Cell Shape
  • Drug Resistance, Neoplasm
  • Epidermal Growth Factor / pharmacology
  • Estrogens / pharmacology
  • Female
  • Humans
  • Hyaluronan Receptors / genetics
  • Hyaluronan Receptors / metabolism
  • Integrin beta1 / metabolism
  • MCF-7 Cells
  • Mice, Nude
  • Neoplasm Invasiveness
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Phenotype
  • RNA Interference
  • Signal Transduction
  • Time Factors
  • Transfection
  • Tumor Microenvironment*
  • Tumor Necrosis Factor-alpha / pharmacology
  • Zinc Finger E-box-Binding Homeobox 1 / genetics
  • Zinc Finger E-box-Binding Homeobox 1 / metabolism


  • CD24 Antigen
  • CD24 protein, human
  • CD44 protein, human
  • Estrogens
  • Hyaluronan Receptors
  • Integrin beta1
  • Tumor Necrosis Factor-alpha
  • ZEB1 protein, human
  • Zinc Finger E-box-Binding Homeobox 1
  • Epidermal Growth Factor