Luminal breast carcinomas usually show imbalanced levels of progesterone receptor (PR) isoforms A (PRA) and B (PRB). The clinical impact of the PRA/PRB ratio remains poorly understood. We have previously demonstrated that tumors with higher levels of PRB than PRA (PRB-H) expressed higher Ki67 and HER2, and lower PR levels than those with higher levels of PRA than PRB (PRA-H). In agreement, transcriptomic studies matched the PRB-H pattern with the luminal B subtype and the PRA-H pattern with the luminal A subtype.
Since, this cohort included samples with different histological types, or HER2 expression, this study aimed to find differential signatures among PRA-H and PRB-H tumors in a homogeneous cohort of samples and select candidates to identify PRA-H tumors. The relevance relies in that only these tumors would respond to an antiprogestin therapy.
Patients are routinely accrued at the Hospital Magdalena V de Martinez, Argentina. Surgery samples are frozen or fixed. Western blots categorize tumors as PRA-H or PRB-H. A total of 18 primary IC-NST tumors (11 PRA-H and 8 PRB-H) passed the control quality to perform a Poly(A) RNA sequencing study.
Among 14,771 genes, 129 were related to the PR isoform imbalance. Various followed the same trend observed previously such as CRISP3 or KRT16. Gene set enrichment analysis showed an up modulation of pathways related to proliferation, such as PI3K/AKT/mTOR and KRAS in PRB-H tumors (Hallmark gene set, NES > 1.7, p < 0.05) and a downmodulation of substrate adhesion and cell junction assembly biological processes in PRA-H tumors, suggesting a more invasive profile (GO biological process, NES < -1.6, p < 0.05).
Finally, we selected a set of 20-40 genes that recapitulate the biological differences observed between both groups that may be used to design a diagnostic panel to predict which patients would respond to an antiprogestin treatment