Human Epididymis Protein 4 (HE4) Expression Loss in Invasive Mammary Carcinoma Is Associated with Aggressive Disease and Adverse Clinical Outcome
EA Slodkowska, CE Sheehan, AB Boguniewicz, CB Sheehan, C Chen, JS Ross. Albany Medical College, Albany, NY
Background: The WFDC2 gene encodes a WAP-type four disulphide core protein with protease activity normally localized to the epithelium of the distal epididymis known as HE4. Transcriptional profiling studies have found consistent up-regulation of HE4 in ovarian cancer and serum-based HE4 testing has recently been introduced as a novel screening method for the disease. The clinico-pathologic significance of HE4 expression in breast cancer has not been previously studied.
Design: Formalin-fixed, paraffin-embedded tissue sections from 146 cases of invasive mammary carcinoma (96 ductal carcinomas (IDC) and 50 lobular carcinomas (ILC) were immunostained by automated methods (Ventana Medical Systems Inc., Tucson, AZ) using rabbit polyclonal HE4 (Covance/Signet, Princeton, New Jersey). Tumors were similarly stained additional ER associated proteins WWP1 (Novus Biologiocals, Littleton, CO) and IGF-1R (Santa Cruz Biotechnology, Santa Cruz, CA) Cytoplasmic immunoreactivity was semiquantitatively scored based on staining intensity and distribution and the results were correlated with morphologic and prognostic variables.
Results: Cytoplasmic staining of benign breast epithelium was universally identified. Cytoplasmic HE4 overexpression was observed in 89/146 (61%) tumors. Tumor HE4 expression significantly correlated with ER positive status [67% ER positive tumors versus 49% ER negative tumors, p=0.035] and HER2 negative status [68% HER2 negative versus 36% HER2 positive, p=0.003]. HE4 expression also correlated with WWP1 expression [75% tumors with WWP1 overexpression versus 51% WWP1 not overexpressed, p=0.004] and IGF-1R [75% tumors with IGF1R overexpression versus 44% IGF1R not overexpressed, p=0.001]. Within the IDC subgroup, HE4 expression correlated with disease recurrence [73% recurrent tumors versus 49% non-recurrent, p=0.02]. On multivariate analysis, young age and advanced stage were independent predictors of recurrence.
Conclusions: HE4 is widely expressed on normal breast ductal and lobular epithelial cells. In breast cancer, expression of HE4 is associated with the ER+/WWP1+/IGF-1R+/HER2 negative subtype and predicts disease recurrence in the IDC sub-group. Further study of HE4 expression as a prognostic factor and potential target of therapy for breast cancer appears warranted.
Monday, March 9, 2009 9:30 AM
Poster Session I Stowell-Orbison/Autopsy Award # 50, Monday Morning