Differential Expression of Heart and Neural Crest Derivatives Expressed Transcript (HAND) 2 in Benign and Neoplastic Endometrium
Rebecca Buell-Gutbrod, Nita Lee, Anthony Montag, Katja Gwin. University of Chicago, Chicago, IL; University of Chicago, Chicago
Background: Approximately 80% of endometrial carcinomas arise through an estrogen dependant pathway (type I carcinomas). In normal endometrium, progesterone inhibits estrogen-mediated proliferation, prevents hyperplasia, and is required for successful pregnancy implantation. Recently, expression of the progesterone induced helix-loop-helix transcription factor (Hand) 2 has been shown to suppress production of fibroblast growth factors (FGFs), the mediators of mitogenic effect of estrogen. In Hand2 knockout mice, continued expression of FGFs lead to persistent stimulation of estrogen-depended pathways and resulted in failed implantation. We hypothesize that Hand2 mediated stomal-epithelial communication also plays a role in the pathogenesis of hyperplasia and endometrial carcinoma.
Design: Archival paraffin embedded material of 62 hysterectomy specimens with a diagnosis of simple and complex hyperplasia, endometrioid, serous, mixed and clear cell carcinoma as well as carcinosarcoma were examined by IHC for expression and localization of Hand2, ER, PR, and Ki-67. Staining was graded for intensity in the stroma and epithelial component. Normal endometrium was used as control.
Results: In secretory and proliferative endometrium, Hand2 exhibits strong nuclear staining in the stroma only; whereas ER and PR show strong expression in glands and stroma. In simple and complex hyperplasia, Hand2 reveals decreased to absent expression adjacent to the abnormal glands. In endometrial carcinomas (type I and II), Hand2 is consistently absent in the stroma surrounding the carcinoma glands. Areas of normal endometrium present in some carcinoma cases showed an abrupt transition with normal stromal expression of Hand2. Comparative analysis of serial sections analyzed for stromal ER, PR, and Ki67 expression revealed consistent downregulation when compared to normal endometrium.
Conclusions: Our study suggests that HAND2 has a function in type I and II uterine carcinoma development due to dysregulated stomal-epithelial signalling. As Hand2 expression is progesterone induced, unbalanced levels of estrogen and progesterone could cause the observed absence of Hand2 adjacent to neoplastic epithelial glands. Loss of Hand2 expression may subsequently lead to lack of suppression of the FGFs, the mediators of the mitogenic effect of estrogen, and support neoplasia. Hand 2 may also explain why progesterone can be successfully used for the treatment of hyperplasia and selected endometrial adenocarcinomas.
Category: Gynecologic & Obstetrics
Tuesday, March 20, 2012 11:15 AM
Platform Session: Section E, Tuesday Morning