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.
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.
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.
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.
CONICET; INC, ANPCYT.
All authors have declared no conflicts of interest.