Downregulation of the Novel Candidate Tumor Suppressor Gene NCOR2/SMRT in Human Breast Cancer Progression.

Abstract

Abstract Background: We recently described a number of DNA copy number changes that differentiated low grade ductal carcinoma in situ (DCIS) lesions with and without associated invasive carcinoma. One of the invasion-associated candidate genes was Nuclear Corepressor 2/Silencing Mediator of Retinoid and Thyroid Receptors (NCOR2/SMRT). This gene is a component of a repressing nuclear receptor complex and a mediator of ER activity. It facilitates recovery from DNA double strand breaks. Previous studies showed that downregulation of the gene was associated with transformation of non-Hodgkin lymphomas.Materials and Methods: Genomic DNA was extracted from microdissected paraffin sections of formalin fixed low grade DCIS lesions with an invasive component (n=42), as well as morphologically similar DCIS lesions without associated invasion within at least 5 years (n=38). Comparative PCR was performed with GAPDH as the reference gene. In addition, we assayed tissue microarrays (TMAs) by immunohistochemistry using two anti-Smrt antibodies. Three TMAs included 162 interpretable cases of invasive breast carcinoma from Roswell Park Cancer Institute (RPCI). One additional TMA included 73 interpretable breast cancers from a previously described cohort from Vienna, Austria. Nuclear staining in neoplastic cells was scored as positive, reduced (significantly weaker compared to admixed benign cells), and negative. Ncor2/Smrt expression was correlated with various patho-biologic variables.Results: Allelic loss of NCOR2/SMRT was observed in 79% (33/42) of DCIS lesions with associated invasion, but in only 26% (10/38) of pure DCIS cases (p<0.01). In the RPCI breast cancer cohort, nuclear Ncor2/Smrt protein was absent or downregulated in 73% (119/162) of tumors. In the Vienna cohort, there was no or markedly reduced nuclear staining in 48% (35/73) of cases. In both cohorts, loss of nuclear reactivity was more common in ER-negative breast cancers. In the Vienna series, Ncor2/Smrt loss was more frequent in PR-negative tumors as well. In the RPCI cohort, Ncor2/Smrt downregulation was more common in ductal (81%, 109/135) than in lobular (37%, 10/27) carcinomas. Neither series showed a significant association between Ncor2/Smrt expression and tumor grade or HER2/neu status.Discussion: Allelic loss of NCOR2/SMRT was significantly more common in DCIS lesions associated with stromal invasion. In invasive tumors, the protein downregulation rate was between 48% and 73%. The gene was more commonly downregulated in ER-negative carcinomas, consistent with its role as a modulator of ER function. Our data provide new evidence that NCOR2/SMRT may play an important part in early breast cancer progression. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3150.