4732 - Progesterone Receptor Isoform Ratio Dictates Antiprogestins/Progestins Effects on Metastatic Breast Cancer Models

Background

The use of progesterone receptor (PR) ligands for adjuvant breast cancer treatment remains controversial. We propose that antiprogestins inhibit the breast tumor growth with high isoform A (PRA)/isoform B (PRB) ratio while progestins may inhibit those with opposite ratios.

Methods

We used metastatic models with different PR isoform ratios to evaluate the effect of antiprogestins [mifepristone (MFP), aglepristone (AGLE), telapristone acetate (TLP), ulipristal acetate (UPA), or progestins [medroxyprogesterone acetate (MPA) or progesterone (Pg)]. Murine BALB/c tumors with PRA>PRB (C7-2-HI) and PRB>PRA (C7-HI), human MDA-MB-231 cells transfected with PRB and the inducible MDA-MB-231-iPRAB cells were inoculated into NSG mice.

Results

All antiprogestins inhibited C7-2-HI tumor growth rate (MFP 88%, TLP 59% UPA 70%) and the onset of lymph node and lung metastasis. AGLE induced complete tumor regression. The progestin MPA, increased tumor size and metastasis in a 60% (p < 0.001) and Pg showed a similar trend (22%). MFP and AGLE also inhibited the tumor growth and number of metastatic foci of the MDA-MB-231-iPRAB expressing PRA. Onset of long-term metastasis was evaluated by tumor surgery after interruption of MFP or AGLE neoadyuvant treatment. Both antiprogestins increased the Disease Free Survival rate (p < 0.001) compared with controls. Six out of 8 and 3/5 mice receiving AGLE and MFP, respectively, are disease free one year after surgery. AGLE adjuvant treatment, also inhibited long-term metastasis (p < 0.001). With C7-HI model (PRB>PRA), AGLE, UPA or MFP increased tumor growth and/or metastasis (p < 0.001) whereas MPA showed an opposite trend in the number of metastatic foci. Experiments performed with the MDA-MB-231 cells transfected with or induced to express PRB confirmed the inhibitory effects of MPA on the metastatic development.

Conclusions

Progestins/antiprogestins stimulate or inhibit, respectively tumor growth/metastasis of mammary carcinomas with high PRA/PRB ratio, and they may exert opposite effects in tumors with low PRA/PRB ratio. These findings highlight the relevance of evaluating PR isofor.m ratio prior to PR ligand treatment on human breast cancer.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

CONICET.

Funding

CONICET; INC, ANPCYT.

Disclosure

All authors have declared no conflicts of interest.