Data from Progesterone Receptor Isoform-Specific Promoter Methylation: Association of <i>PRA</i> Promoter Methylation with Worse Outcome in Breast Cancer Patients

Abstract

<div>Abstract<p><b>Purpose:</b> ERα and PR levels are critical determinants for breast cancer prognosis and response to endocrine therapy. Although <i>PR</i> is known to be silenced by methylation of its promoter, few studies have correlated methylation with PR levels and outcome in breast cancer. There is only one previous small study comparing methylation of the two PR isoforms, <i>PRA</i> and <i>PRB</i>, which are expressed from different promoters, and finally, there is no prior knowledge of associations between isoform-specific methylation and outcome.</p><p><b>Experimental Design:</b> We conducted a cohort-based study to test for associations between <i>PRA</i> and <i>PRB</i> methylation, expression, and clinical outcome in tamoxifen-treated patients (<i>n</i> = 500), and in patients who underwent surgery only (<i>n</i> = 500). Methylation and PR levels were measured by bisulfite pyrosequencing and ligand-binding assay, respectively.</p><p><b>Results:</b> Low PR levels were significantly associated with worse outcome in all patients. <i>PRA</i> and <i>PRB</i> promoters were methylated in 9.6% and 14.1% of the breast tumors, respectively. The majority (74%) of PR-negative tumors were not methylated despite the significant inverse correlation of methylation and PR levels. <i>PRA</i> methylation was significantly associated with <i>PRB</i> methylation, although a subset of tumors had <i>PRA</i> only (3.9%) or <i>PRB</i> only (8.3%) methylated. Methylation of <i>PRA</i>, but not <i>PRB</i> was significantly associated with worse outcome in the tamoxifen-treated group.</p><p><b>Conclusions:</b> Mechanisms other than promoter methylation may be more dominant for loss of PR. Isoform-specific methylation events suggest independent regulation of <i>PRA</i> and <i>PRB</i>. Finally, this article shows for the first time that <i>PRA</i> methylation plays a unique role in tamoxifen-resistant breast cancer. <i>Clin Cancer Res; 17(12); 4177–86. ©2011 AACR</i>.</p></div>