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

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

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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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