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

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.

• Authors: María Florencia Abascal, Andrés Elia, Michelle Alvarez, Gabriela Pataccini, Gonzalo Sequeira, Marina Riggio, Virginia Figueroa, Caroline A Lamb, Paola A Rojas, Eunice Spengler, Paula Martínez-Vazquez, Javier Burruchaga, Marcos Liguori, Ana Sahores, Victoria Wargon, Alfredo Molinolo, Stephen Hewitt, Marc Lombes, Carol Sartorius, Silvia Inés Vanzulli, Sebastián Giulianelli, Claudia Lanari
• Journal: International journal of cancer (Int J Cancer) Vol. 150 Issue 9 Pg. 1481-1496 (05 01 2022) ISSN: 1097-0215 [Electronic] United States
• PMID: 34935137 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 UICC.

Chemical References

• Cell Cycle Proteins
• Intracellular Signaling Peptides and Proteins
• N-myc downstream-regulated gene 1 protein
• Progestins
• Protein Isoforms
• Receptors, Progesterone
• Progesterone

Topics

• Animals
• Breast Neoplasms (pathology)
• Cell Cycle Proteins (metabolism)
• Female
• Humans
• Intracellular Signaling Peptides and Proteins (metabolism)
• Mice
• Neoplasm Metastasis
• Progesterone (pharmacology)
• Progestins (metabolism)
• Protein Isoforms (metabolism)
• Receptors, Progesterone (metabolism)