Keratin 17 is a negative prognostic biomarker in high-grade endometrial carcinomas

Highlights

• Keratin 17 is a biomarker for poor survival in high-grade endometrial cancers.

• Keratin 17 is predominantly localized to the cytoplasm of endometrial cancer cells.

• Keratin 17 is expressed only in the epithelial component of endometrial cancer.

• The prognostic value of keratin 17 is independent of tumor stage and patient age.

Summary

Keratin 17 (K17) has been established as a negative prognostic biomarker in cervical and ovarian cancers but has not previously been evaluated as a prognostic biomarker in endometrial adenocarcinoma. The association of K17 with decreased patient survival may be explained in part by the discovery that K17 drives tumor aggression by serving as a nuclear shuttle of p27, leading to cell cycle progression and tumor growth. The current study tests the hypothesis that K17 mRNA and protein levels correlate with decreased survival of patients with high-grade endometrial cancer. Gene expression data (mRNA) from The Cancer Genome Atlas were analyzed for 271 high-grade endometrial carcinomas and K17 immunohistochemistry (IHC) was performed on a separate cohort of 119 high-grade endometrial cancer cases from two academic medical centers. Survival analyses were determined by Cox proportional hazards regression. High K17 mRNA and IHC correlated with decreased overall survival (HR: 1.8, P = .0101, HR: 1.8, P = .0488, respectively). K17 was positive in malignant glandular cells of the endometrium but not in other tissues, including endometrial stroma, myometrium and uterine sarcoma. These results support the conclusion that K17 is a negative prognostic biomarker in high-grade endometrial carcinoma and that K17 IHC test results could be used to inform decisions related to therapeutic intervention.

Introduction

There is an unmet need to identify prognostic markers in high-grade endometrial adenocarcinoma that could provide information to help guide treatment and to provide more accurate predictions of patient outcomes. In the United States, endometrial cancer is the most common gynecologic malignancy [1]. Low-grade endometrial cancers are often caused by estrogen excess and account for approximately 80% of all uterine cancers. Patients with these low-grade tumors have a favorable prognosis. High-grade tumors, in contrast, are estrogen-independent and often have a poor prognosis [[2], [3], [4]]. While disease stage and histology largely dictate prognosis, patients with similar stage and grade can vary greatly in their survival outcomes [5]. The current standard-of-care treatment for patients with endometrial cancer is hysterectomy, with or without adjuvant chemotherapy. Categorizing patients based on disease aggression can help clinicians make more insightful decisions regarding the appropriate treatment option. Patients with aggressive disease should be closely monitored while patients with more indolent disease should be spared of unnecessary tests or interventions. Therefore, there remains a need to identify novel prognostic biomarkers in endometrial adenocarcinoma.

One potential candidate is keratin 17 (K17), which has been demonstrated to be a powerful negative prognostic biomarker in several cancers, including other tumors of the female genital tract (cervical squamous cell carcinoma, endocervical adenocarcinoma, and surface epithelial-derived ovarian carcinomas), triple negative breast cancer, gastric adenocarcinoma, oropharyngeal squamous cell carcinoma, and pancreatic adenocarcinoma [[6], [7], [8], [9], [10], [11], [12]]. K17 is an intermediate filament protein that is normally expressed in the ectodermal germ layer during embryogenesis but is silenced in most adult somatic tissues [13]. Mechanistic studies demonstrated that in response to mitogenic signaling, K17 translocates into the nucleus via a nuclear localization signal, where it binds to p27, a G₁-S cell cycle inhibitor. The p27-K17 complex is then exported into the cytoplasm, where p27 is degraded, leading to sustained cell cycle progression [14]. Additionally, in vivo murine models showed that the absence of K17 inhibited the progression of cervical dysplasia and tumor growth, further supporting our previous findings that high expression of K17 is prognostic for reduced survival in cervical cancer [14,15]. These observations prompted our current study to test the hypothesis that higher levels of K17 mRNA and immunohistochemical staining for K17 are associated with decreased survival of patients with high-grade endometrial carcinoma.