Progesterone receptor isoform ratio: a breast cancer prognostic and predictive factor for antiprogestin responsiveness

Abstract

<b>Background:</b> Compelling evidence shows that progestins regulate breast cancer growth. Using preclinical models, we demonstrated that antiprogestins are inhibitory when the level of progesterone receptor isoform A (PR-A) is higher than that of isoform B (PR-B) and that they might stimulate growth when PR-B is predominant. The aims of this study were to investigate ex vivo responses to mifepristone (MFP) in breast carcinomas with different PR isoform ratios and to examine their clinical and molecular characteristics. <b>Methods:</b> We performed human breast cancer tissue culture assays (n = 36) to evaluate the effect of MFP on cell proliferation. PR isoform expression was determined by immunoblotting (n = 282). Tumors were categorized as PRA-H (PR-A/PR-B ≥ 1.2) or PRB-H (PR-A/PR-B ≤ 0.83). RNA was extracted for Ribo-Zero-Seq sequencing to evaluate differentially expressed genes. Subtypes and risk scores were predicted using the PAM50 gene set, the data analyzed using The Cancer Genome Atlas RNA-seq gene analysis and other publicly available gene expression data. Tissue microarrays were performed using paraffin-embedded tissues (PRA-H n = 53, PRB-H n = 24), and protein expression analyzed by immunohistochemistry. All statistical tests were two-sided. <b>Results:</b> One hundred sixteen out of 222 (52.3%) PR+ tumors were PRA-H, and 64 (28.8%) PRB-H. Cell proliferation was inhibited by MFP in 19 of 19 tissue cultures from PRA-H tumors. A total of 139 transcripts related to proliferative pathways were differentially expressed in nine PRA-H and seven PRB-H tumors. PRB-H and PRA-H tumors were either luminal B or A phenotypes, respectively (P =.03). PRB-H cases were associated with shorter relapse-free survival (hazard ratio [HR] = 2.70, 95% confidence interval [CI] = 1.71 to 6.20, P =.02) and distant metastasis-free survival (HR = 4.17, 95% CI = 2.18 to 7.97, P <.001). PRB-H tumors showed increased tumor size (P <.001), Ki-67 levels (P <.001), human epidermal growth factor receptor 2 expression (P =.04), high grades (P =.03), and decreased total PR (P =.004) compared with PRA-H tumors. MUC-2 (P <.001) and KRT6A (P =.02) were also overexpressed in PRB-H tumors. <b>Conclusion:</b> The PRA/PRB ratio is a prognostic and predictive factor for antiprogestin responsiveness in breast cancer.