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

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

  • Int J Cancer. 2022 May 1;150(9):1481-1496. doi: 10.1002/ijc.33913.
María Florencia Abascal 1,  Andrés Elia 1,  Michelle Alvarez 1 2,  Gabriela Pataccini 1,  Gonzalo Sequeira 1 3,  Marina Riggio 1,  Virginia Figueroa 1,  Caroline A Lamb 1,  Paola A Rojas 1,  Eunice Spengler 4,  Paula Martínez-Vazquez 4,  Javier Burruchaga 4,  Marcos Liguori 4,  Ana Sahores 1,  Victoria Wargon 1,  Alfredo Molinolo 5,  Stephen Hewitt 6,  Marc Lombes 7,  Carol Sartorius 8,  Silvia Inés Vanzulli 9,  Sebastián Giulianelli 1 10,  Claudia Lanari 1
Affiliations

Affiliations

  • 1 Instituto de Biología y Medicina Experimental (IBYME), CONICET, Buenos Aires, Argentina.
  • 2 Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
  • 3 Hospital Público de Gestión Descentralizada Dr. Arturo Oñativia, Salta, Argentina.
  • 4 Hospital de Agudos "Magdalena V de Martínez", General Pacheco, Buenos Aires, Argentina.
  • 5 Moores Cancer Center, UCSD, La Jolla, California, USA.
  • 6 National Cancer Institute, NIH, Bethesda, Maryland, USA.
  • 7 INSERM and Fac Med Paris-Sud, Université Paris Saclay, UMR-S 1185, Le Kremlin-Bicêtre, France.
  • 8 Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA.
  • 9 Academia Nacional de Medicina, Buenos Aires, Argentina.
  • 10 Instituto de Biología de Organismos Marinos, IBIOMAR-CCT CENPAT-CONICET, Puerto Madryn, Argentina.
PMID: 34935137 DOI: 10.1002/ijc.33913
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.

Keywords

NDRG1; antimetastatic growth; progesterone receptor isoforms; progestin.

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