Cytokeratin 5-Positive Cells Represent a Therapy Resistant subpopulation in Epithelial Ovarian Cancer

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.