Progesterone receptor isoform ratio dictates antiprogestin/progestin effects on breast cancer growth and metastases: A role for NDRG1

ABASCAL, MARÍA FLORENCIA; PATACCINI, GABRIELA; ELIA, ANDRÉS; FIGUEROA, VIRGINIA; SEQUEIRA, GONZALO; SPENGLER, EUNICE; LAMB, CAROLINE A.; LIGUORI, MARCOS; MARTÍNEZ-VAZQUEZ, PAULA; MOLINOLO, ALFREDO; SARTORIUS, CAROL; SAHORES, ANA; LANARI, CLAUDIA; HEWITT, STEPHEN; VANZULLI, SILVIA INÉS; ALVAREZ, MICHELLE; RIGGIO, MARINA; ROJAS, PAOLA A.; BURRUCHAGA, JAVIER; WARGON, VICTORIA; LOMBES, MARC; GIULIANELLI, SEBASTIÁN

INTERNATIONAL JOURNAL OF CANCER. JOURNAL INTERNATIONAL DU CANCER.

JOHN WILEY & SONS INC

Año: 2022 vol. 150 p. 1481 - 1496

0020-7136

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.