Progesterone Receptor (PR) Promoter Methylation – Role as a Predictive and Prognostic Marker in Breast Cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 69; no. 24_Supplement; p. 2002
• Main Authors: Pathiraja, T., Jelinek, J., He, R., Shetty, P., Hartmaier, R., Margossian, A., Hilsenbeck, S., Issa, J., Oesterreich, S.
• Format: Journal Article
• Language: English
• Published: 15.12.2009
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.SABCS-09-2002

Abstract Estrogen receptor α expression is a well known and clinically utilized predictor of endocrine treatment response. In addition, loss of expression of the progesterone receptor (PR), an estrogen induced gene, has been shown to be associated with resistance to endocrine therapy. PR is known to be epigenetically regulated by DNA methylation, but only a few studies have correlated PR DNA methylation with its expression in breast cancer. Previous studies are contradictory and have been limited by small sample size. There is also evidence that differential expression of the two PR isoforms, PRA and PRB, might contribute to breast tumorigenesis, and altered hormone response. Whether PRA and/or PRB DNA methylation could predict response to endocrine therapy remains an open question. Further, there are no published studies so far testing whether PRA and/or PRB methylation have prognostic significance.Our objective was 1) to determine whether there was an association between PRA and/or PRB methylation levels with total PR expression in breast tumors, and 2) to determine if PRA and/or PRB methylation would have predictive and/or prognostic value. For this study, we utilized tumor DNA from patients with ER-positive breast tumors which were treated with adjuvant tamoxifen after surgery (n=500), and from patients treated with surgery only (n=500). PR expression was determined by ligand binding assay, and PRA and PRB promoter methylation was measured by bisulfite pyrosequencing.Both PRA and PRB methylation were significantly (p<0.0001) associated with PR expression, in an inverse relationship. Low PR expression was significantly (p=0.02) associated with worse overall survival (OS), and there was a trend towards shorter disease free survival (DFS) in the tamoxifen treated group. There was no association between PR expression and survival in the untreated group. PRA methylation was significantly (p<0.0001) associated with PRB methylation. Intriguingly, increased PRA methylation was significantly associated with shorter DFS (p=0.047) and OS (p=0.0067) in tamoxifen treated patients, and with shorter OS (p=0.008) in the untreated patients. In contrast, there was no significant association between PRB methylation and survival in either tamoxifen treated or untreated patients.Our results show that PR expression is significantly associated with PR methylation. The data suggest that PRA methylation is a predictive marker for tamoxifen response and also a prognostic marker for breast cancer progression. This is the largest study so far to elucidate the association of PRA and PRB methylation with PR status, response to tamoxifen, and tumor prognosis, and we believe that it provides useful insights into the role of PR methylation in breast tumorigenesis. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2002.