Artículo
Progesterone receptor isoform ratio dictates antiprogestin/progestin effects on breast cancer growth and metastases: A role for NDRG1
Abascal, Maria Florencia
; Elia, Andres Maximiliano
; Alvarez, Michelle; Pataccini, Gabriela
; Sequeira, Gonzalo Ricardo
; Riggio, Marina
; Figueroa, Virginia
; Lamb, Caroline Ana
; Rojas, Paola Andrea
; Spengler, Eunice; Martínez Vazquez, Paula; Burruchaga, Javier; Liguori, Marcos Daniel; Sahores, Ana
; Wargon, Victoria
; Molinolo, Alfredo; Hewitt, Stephen M.; Lombes, Marc; Sartorius, Carol; Vanzulli, Silvia; Giulianelli, Sebastián; Lanari, Claudia Lee Malvina
Fecha de publicación:
2021
Editorial:
John Wiley & Sons Inc.
Revista:
International Journal of Cancer. Journal International du Cancer
ISSN:
0020-7136
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
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.
Palabras clave:
PROGESTERONE RECEPTOR ISOFORMS
,
METASTATIC GROWTH
,
NDRG1
,
PROGESTIN
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Colecciones
Articulos(IBYME)
Articulos de INST.DE BIOLOGIA Y MEDICINA EXPERIMENTAL (I)
Articulos de INST.DE BIOLOGIA Y MEDICINA EXPERIMENTAL (I)
Citación
Abascal, Maria Florencia; Elia, Andres Maximiliano; Alvarez, Michelle; Pataccini, Gabriela; Sequeira, Gonzalo Ricardo; et al.; Progesterone receptor isoform ratio dictates antiprogestin/progestin effects on breast cancer growth and metastases: A role for NDRG1; John Wiley & Sons Inc.; International Journal of Cancer. Journal International du Cancer; 150; 9; 2021; 1481-1496
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