Breast Cancer Research and Treatment

, Volume 128, Issue 1, pp 45–55 | Cite as

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

  • Peter Kabos
  • James M. Haughian
  • Xinshuo Wang
  • Wendy W. Dye
  • Christina Finlayson
  • Anthony Elias
  • Kathryn B. Horwitz
  • Carol A. Sartorius
Preclinical study


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 ERPR 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 ERPRCK5+ 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.


Tumor-initiating cells Estrogen receptors Endocrine therapy Tamoxifen Cytokeratin 5 Breast cancer 



Aromatase inhibitor


Aldehyde dehydrogenase 1








Three dimensional






Epidermal growth factor receptor


Estrogen receptor




Epithelial specific antigen


Estrogen withdrawal


Fetal bovine serum




Human epidermal growth factor receptor 2








Medroxyprogesterone acetate


Progesterone receptor


Sodium deoxycholate




Tumor initiating cell


Triple negative phenotype



This work was supported by grants from the American Society of Clinical Oncology YIA-PN200810-161 (P. Kabos), National Institutes of Health 1 F32 CA142096-01 (J.M. Haughian), Martha Cannon Dear Professorship (A. Elias), National Institutes of Health R01 CA26869 (K.B. Horwitz), Breast Cancer Research Foundation (K.B. Horwitz), the National Foundation for Cancer Research (K.B. Horwitz), The Avon Foundation (K.B. Horwitz), The Avon Foundation (C.A. Sartorius), and the University of Colorado Cancer Center (C.A. Sartorius).

Conflicts of interest

The authors have no conflicts of interest to disclose.


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Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Peter Kabos
    • 1
  • James M. Haughian
    • 2
  • Xinshuo Wang
    • 2
  • Wendy W. Dye
    • 2
  • Christina Finlayson
    • 3
  • Anthony Elias
    • 1
  • Kathryn B. Horwitz
    • 2
    • 4
  • Carol A. Sartorius
    • 2
  1. 1.Division of Medical Oncology, Department of MedicineUniversity of Colorado Anschutz Medical CampusAuroraUSA
  2. 2.Division of Endocrinology, Metabolism, and Diabetes, Department of MedicineUniversity of Colorado Anschutz Medical CampusAuroraUSA
  3. 3.Department of Surgery, Department of MedicineUniversity of Colorado Anschutz Medical CampusAuroraUSA
  4. 4.Department of PathologyUniversity of Colorado Anschutz Medical CampusAuroraUSA

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