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Cytokeratin 5–Positive Cells Represent a Therapy Resistant subpopulation in Epithelial Ovarian Cancer
  1. Bradley R. Corr, MD*,
  2. Jessica Finlay-Schultz, PhD,
  3. Rachel B. Rosen,
  4. Lubna Qamar*,
  5. Miriam D. Post, MD,
  6. Kian Behbakht, MD*,
  7. Monique A. Spillman, MD, PhD and
  8. Carol A. Sartorius, PhD
  1. *Departments of Obstetrics and Gynecology and
  2. Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO; and
  3. Texas Oncology, Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX.
  1. Address correspondence and reprint requests to Bradley R. Corr, MD, Department of Gynecologic Oncology, University of Colorado Anschutz Medical Campus, 12631 E. 17th Ave Campus Box B198-6, Aurora, CO 80045. E-mail: Bradley.Corr{at}ucdenver.edu; Carol A. Sartorius, PhD, Department of Pathology, University of Colorado Anschutz Medical Campus, 12801 E. 17th Ave Mail Stop 8104, Aurora, CO 80045. E-mail: Carol.Sartorius{at}ucdenver.edu.

Abstract

Objective Cytokeratin 5 (CK5) is an epithelial cell marker implicated in stem and progenitor cell activity in glandular reproductive tissues and endocrine and chemotherapy resistance in estrogen receptor (ER)+ breast cancer. The goal of this study was to determine the prevalence of CK5 expression in ovarian cancer and the response of CK5+ cell populations to cisplatin therapy.

Materials and Methods Cytokeratin 5 expression was evaluated in 2 ovarian tissue microarrays, representing 137 neoplasms, and 6 ovarian cancer cell lines. Cell lines were treated with IC50 (half-maximal inhibitory concentration) cisplatin, and the prevalence of CK5+ cells pretreatment and posttreatment was determined. Proliferation of CK5+ versus CK5 cell populations was determined using 5-bromo-2′-deoxyuridine incorporation. Chemotherapy-induced apoptosis in CK5+ versus CK5 cells was measured using immunohistochemical staining for cleaved caspase-3.

Results Cytokeratin 5 was expressed in 39.3% (42 of 107) of epithelial ovarian cancers with a range of 1% to 80% positive cells. Serous and endometrioid histologic subtypes had the highest percentage of CK5+ specimens. Cytokeratin 5 expression correlated with ER positivity (38 of 42 CK5+ tumors were also ER+). Cytokeratin 5 was expressed in 5 of 6 overall and 4 of 4 ER+ epithelial ovarian cancer cell lines ranging from 2.4% to 52.7% positive cells. Cytokeratin 5+ compared with CK5 cells were slower proliferating. The prevalence of CK5+ cells increased after 48-hour cisplatin treatment in 4 of 5 cell lines tested. Cytokeratin 5+ ovarian cancer cells compared with CK5 ovarian cancer cells were more resistant to cisplatin-induced apoptosis.

Conclusions Cytokeratin 5 is expressed in a significant proportion of epithelial ovarian cancers and represents a slower proliferating chemoresistant subpopulation that may warrant cotargeting in combination therapy.

  • Epithelial ovarian cancer
  • Cytokeratin 5
  • Cisplatin
  • Drug resistance
  • Estrogen receptors

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Footnotes

  • This work was supported by a University of Colorado AMC Department of Obstetrics and Gynecology fellowship (B.R.C.) and NIH RO1 CA140985 (C.A.S.). J.F.S. was supported by NIH 1F32CA177081. The University of Colorado AMC Tissue Biobanking and Processing Shared Resource was supported by P30CA046934.

  • The authors declare no conflicts of interest.

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