Cytokeratin 5 positive cells represent a steroid receptor negative and therapy resistant subpopulation in luminal breast cancers

Breast Cancer Res Treat. 2011 Jul;128(1):45-55. doi: 10.1007/s10549-010-1078-6. Epub 2010 Jul 28.


A majority of breast cancers are estrogen receptor (ER) positive and have a luminal epithelial phenotype. However, these ER⁺ tumors often contain heterogeneous subpopulations of ER⁻ tumor cells. We previously identified a population of cytokeratin 5 (CK5) positive cells within ER⁺ and progesterone receptor positive (PR⁺) tumors that is both ER⁻PR⁻ and CD44⁺, a marker of breast tumor-initiating cells (TICs). These CK5⁺ cells have properties of TICs in luminal tumor xenografts, and we speculated that they are more resistant to chemo- and anti-ER-targeted therapies than their ER⁺ neighbors. To test this, we used ER⁺PR⁺ T47D and MCF7 breast cancer cells. CK5⁺ cells had lower proliferative indices than CK5⁻ cells, were less sensitive to 5-fluorouracil and docetaxel, and cultures became enriched for CK5⁺ cells after treatments. CK5⁺ cells were less prone to drug-induced apoptosis than CK5⁻ cells. In cells treated with 17β-estradiol (E) plus anti-estrogens tamoxifen or fulvestrant, ER protein levels decreased, and CK5 protein levels increased, compared to controls treated with E alone. In ER⁺ tumors from patients treated with neoadjuvant endocrine therapies ER gene expression decreased, and CK5 gene expression increased in post compared to pre-treatment tumors. The number of CK5⁺ cells in tumors also increased in post- compared to pre-treatment tumors. We conclude that an ER⁻PR⁻CK5⁺ subpopulation found in many luminal tumors is resistant to standard endocrine and chemotherapies, relative to the majority ER⁺PR⁺CK5⁻ cells. Compounds that effectively target these cells are needed to improve outcome in luminal breast cancers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Hormonal / pharmacology
  • Apoptosis / drug effects
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Drug Resistance, Neoplasm*
  • Estradiol / analogs & derivatives
  • Estradiol / pharmacology
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Female
  • Fulvestrant
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Keratin-5 / genetics
  • Keratin-5 / metabolism*
  • Neoadjuvant Therapy
  • Phenotype
  • Receptors, Progesterone / metabolism*
  • Tamoxifen / pharmacology


  • Antineoplastic Agents, Hormonal
  • ESR1 protein, human
  • Estrogen Receptor alpha
  • KRT5 protein, human
  • Keratin-5
  • Receptors, Progesterone
  • Tamoxifen
  • Fulvestrant
  • Estradiol