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.

Metabolic Adaptations in an Endocrine-Related Breast Cancer Mouse Model Unveil Potential Markers of Tumor Response to Hormonal Therapy

“…In HIR tumors, the lowest GPC levels (within the tumors) again seems to reflect a distinct status of membrane metabolism where lower GPC may be the result of higher phospholipid (phosphatidylcholine, main membrane constituent) synthesis. Again, potentially different metastatic status may relate to the signature differences described above, although such feature could not be evaluated for HIR tumors, due to their rapid growth and subsequent early sacrifice of the animals (before metastasis could occur or be detected) ( 76 ). This possible relationship between metabolite signatures and tumor metastatic status is of large interest in BC research and requires further investigation.…”

Beneficial Effects of Mifepristone Treatment in Patients with Breast Cancer Selected by the Progesterone Receptor Isoform Ratio: Results from the MIPRA Trial

“…Aromatase inhibitors or ER degraders may not work together with mifepristone, because they inhibit PR expression. Because we have already shown that lymph node metastases maintain the same PR isoform ratio as the primary tumor ( 15 ), it may be speculated that this treatment might prove suitable in an adjuvant setting, or alternatively, in a neoadjuvant setting, if further immunotherapy is suggested. Ongoing studies are currently evaluating the combination of mifepristone and CDK4/6 inhibitors in preclinical PRA-H models.…”

“…Moreover, in vitro , mifepristone exerts antiproliferative effects only in PRA-H+ cells ( 16 ), suggesting that the direct antiprogestin effect of mifepristone is the prevailing effect, without ruling out a contribution from its antiglucocorticoid or its antiandrogenic effects (reviewed in ref. 15 ).…”

“… 3 ). Preclinical studies ( 3, 14, 15 ) and human breast cancer samples cultured ex vivo ( 16 ) showed that tumors with a high PRA/PRB ratio (PRA-H) are antiprogestin-responsive tumors and that those with the opposite ratio (PRB-H) may show mild responses, no response, or may even be stimulated to proliferate or metastasize under this treatment ( 15 ).…”

Molecular characterization of breast cancer cell pools with normal or reduced ability to respond to progesterone: a study based on RNA-seq

“…The ratio of the two PR isoforms, PR-A and PR-B, may be predictive for progestin and antiprogestin response. Breast cancers with high PR-A/PR-B ratios metastatic growth was inhibited by antiprogestins, and the metastatic growth of breast cancers with low PR-A/PR-B ratios was inhibited with progestins [ 22 , 23 ].…”