Progesterone receptor isoform ratio to define the molecular signature of luminal breast cancers and their antiprogestin responsiveness

MARIA MAY; PAOLA ROJAS; GONZALO SEQUEIRA, ANDRES; ANDRES ELIA; PAULA MARTINEZ VAZQUEZ; PEDRO GONZALEZ; ALFREDO MOLINOLO; STEPHEN M. HEWITT; CHARLES M. PEROU; HUGO GASS; CLAUDIA LANARI

Chicago

Congreso; 2015 ASCO Annual Meeting; 2015

Background: Current therapies for hormone receptor (+) breast carcinomas target the estrogen receptor. Evidence indicates that the progesterone receptor (PR) also participates in cancer growth. In experimental models, we showed that mifepristone (MFP) inhibits the growth of mammary carcinomas when the predominant isoform is PR-A. The aim of our study was to confirm these observations and explore the molecular signatures of breast cancers overexpressing isoforms PR-B or PR-A.Methods: Tissue sections from 100 surgical samples were cultured with MFP (10 nM) or vehicle for 48 hs, and embedded in paraffin for Ki-67 staining. Frozen samples were processed for Western blotting (n = 360) or RNAseq (n = 16). Patients were considered PR-A(+) if PR-A/PR-B ≥ 1.2, or PR-B(+) if PR-A/PR-B ≤ 0.83. The sample size required to detect a 50% difference in MFP response between PR-A+ vs. non PR-A+ samples (type I error: 5%; type II error: 10%) was 19 patients/group. Results: MFP only inhibited Ki-67 expression in PR-A+ samples (p < 0.001). The 9 ductal HER2 (-) cancer samples analyzed by RNA-Seq with the EBseq algorithm showed 140 transcripts (FC > ±2; FDR < 0.05); 55 up-regulated in PR-A, and 85 in PR-B. Gene ontology showed functional modules associated with cancer cell proliferation such as 'Aurora B signaling' and the 'FOXM1 transcription factor network' (p < 0.01) linked with PR-B up-modulated genes. Intrinsic subtypes and risk score (ROR-S) predicted by the 50-gene PAM50 model were associated with each PR isoform group; 4/4 PR-B cases were Luminal B and 4/5 PR-A were Luminal A (p < 0.01). Studies of 140 deregulated transcripts discriminating PR-A from PR-B (TCGA RNASeq breast cancer dataset) demonstrated that a large number of genes up-regulated in PR-B group, remained up-regulated in luminal B and basal-like cancers, compared with PR-A associated genes that are expressed in normal-like and luminal A subtypes. The gene expression signatures associated to each PR isoform are now under validation using an independent cohort of breast cancer samples. Conclusions: The PR isoform ratio may define subgroups within the luminal breast cancers: those with PR-A/PR-B ≥ 1.2 are candidates for MFP treatment.