Progesterone receptor isoform ratio dictates antiprogestin/progestin effects on breast cancer growth and metastases: A role for NDRG1. Issue 9 (13th January 2022)

• Record Type: Journal Article
• Authors: Abascal, María Florencia; Elia, Andrés; Alvarez, Michelle; Pataccini, Gabriela; Sequeira, Gonzalo; Riggio, Marina; Figueroa, Virginia; Lamb, Caroline A.; Rojas, Paola A.; Spengler, Eunice; Martínez‐Vazquez, Paula; Burruchaga, Javier; Liguori, Marcos; Sahores, Ana; Wargon, Victoria; Molinolo, Alfredo; Hewitt, Stephen; Lombes, Marc; Sartorius, Carol; Vanzulli, Silvia Inés; Giulianelli, Sebastián; Lanari, Claudia
• Is Part Of: International journal of cancer. Volume 150:Issue 9(2022)
• Page Start: 1481
• Page End: 1496
• Publication Date: 2022-01-13
• Subjects: antimetastatic growth -- NDRG1 -- progesterone receptor isoforms -- progestin; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.33913
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract: Progesterone receptors (PRs) ligands are being tested in luminal breast cancer. There are mainly two PR isoforms, PRA and PRB, and their ratio (PRA/PRB) may be predictive of antiprogestin response. Our aim was to investigate: the impact of the PR isoform ratio on metastatic behaviour, the PR isoform ratio in paired primary tumours and lymph node metastases (LNM) and, the effect of antiprogestin/progestins on metastatic growth. Using murine and human metastatic models, we demonstrated that tumours with PRB > PRA (PRB‐H) have a higher proliferation index but less metastatic ability than those with PRA > PRB (PRA‐H). Antiprogestins and progestins inhibited metastatic burden in PRA‐H and PRB‐H models, respectively. In breast cancer samples, LNM retained the same PRA/PRB ratio as their matched primary tumours. Moreover, PRA‐H LNM expressed higher total PR levels than the primary tumours. The expression of NDRG1, a metastasis suppressor protein, was higher in PRB‐H compared to PRA‐H tumours and was inversely regulated by antiprogestins/progestins. The binding of the corepressor SMRT at the progesterone responsive elements of the NDRG1 regulatory sequences, together with PRA, impeded its expression in PRA‐H cells. Antiprogestins modulate the interplay between SMRT and AIB1 recruitment in PRA‐H or PRB‐H contexts regulating NDRG1 expression and thus, metastasis. In conclusion, we provide a mechanistic interpretation to explain the differential role of PR isoforms in metastatic growth and highlight the therapeutic benefit of using antiprogestins in PRA‐H tumours. The therapeutic effect of progestins in PRB‐H tumours is suggested. Abstract : What's new? The effect of progesterone receptors (PR) ligands on tumour growth has mostly been investigated in non‐metastatic luminal breast cancer models. This study shows that antiprogestins and progestins inhibit the metastatic growth of luminal mammary carcinomas with high and low PRA/PRB ratios, respectively. The authors provide a mechanistic interpretation of how the metastasis suppressor protein NDRG1 may mediate the differential metastatic potential of tumours with different PR isoform levels. Moreover, lymph node metastases retain the same PR isoform profile as their matched primary tumours, suggesting that PR ligands might be useful in treating patients even in adjuvant settings.