Breast Cancer Research and Treatment

, Volume 128, Issue 1, pp 45–55

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

Authors

  • Peter Kabos
    • Division of Medical Oncology, Department of MedicineUniversity of Colorado Anschutz Medical Campus
  • James M. Haughian
    • Division of Endocrinology, Metabolism, and Diabetes, Department of MedicineUniversity of Colorado Anschutz Medical Campus
  • Xinshuo Wang
    • Division of Endocrinology, Metabolism, and Diabetes, Department of MedicineUniversity of Colorado Anschutz Medical Campus
  • Wendy W. Dye
    • Division of Endocrinology, Metabolism, and Diabetes, Department of MedicineUniversity of Colorado Anschutz Medical Campus
  • Christina Finlayson
    • Department of Surgery, Department of MedicineUniversity of Colorado Anschutz Medical Campus
  • Anthony Elias
    • Division of Medical Oncology, Department of MedicineUniversity of Colorado Anschutz Medical Campus
  • Kathryn B. Horwitz
    • Division of Endocrinology, Metabolism, and Diabetes, Department of MedicineUniversity of Colorado Anschutz Medical Campus
    • Department of PathologyUniversity of Colorado Anschutz Medical Campus
    • Division of Endocrinology, Metabolism, and Diabetes, Department of MedicineUniversity of Colorado Anschutz Medical Campus
Preclinical study

DOI: 10.1007/s10549-010-1078-6

Cite this article as:
Kabos, P., Haughian, J.M., Wang, X. et al. Breast Cancer Res Treat (2011) 128: 45. doi:10.1007/s10549-010-1078-6

Abstract

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.

Keywords

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

Abbreviations

AI

Aromatase inhibitor

ALDH1

Aldehyde dehydrogenase 1

BrdU

5-Bromo-2-deoxyuridine

CK

Cytokeratin

2D

Two-dimensional

3D

Three dimensional

DAPI

4′,6-Diamidino-2-phenylindole

Dx

Docetaxel

EGFR

Epidermal growth factor receptor

ER

Estrogen receptor

E

17β-estradiol

ESA

Epithelial specific antigen

EWD

Estrogen withdrawal

FBS

Fetal bovine serum

5-FU

5-Fluorouracil

HER2

Human epidermal growth factor receptor 2

ICC

Immunocytochemistry

IHC

Immunohistochemistry

Lin

Lineage

MPA

Medroxyprogesterone acetate

PR

Progesterone receptor

SOC

Sodium deoxycholate

Tam

4-Hydroxytamoxifen

TIC

Tumor initiating cell

TNP

Triple negative phenotype

Copyright information

© Springer Science+Business Media, LLC. 2010