title: Progesterone Receptor Isoform Ratio: A Breast Cancer Prognostic and Predictive Factor for Antiprogestin Responsiveness.
abstract: Compelling evidence shows that progestins regulate breast cancer growth. Using preclinical models, we demonstrated that antiprogestins are inhibitory when the level of progesterone receptor isoform A (PR-A) is higher than that of isoform B (PR-B) and that they might stimulate growth when PR-B is predominant. The aims of this study were to investigate ex vivo responses to mifepristone (MFP) in breast carcinomas with different PR isoform ratios and to examine their clinical and molecular characteristics.
  
  
  
  We performed human breast cancer tissue culture assays (n = 36) to evaluate the effect of MFP on cell proliferation. PR isoform expression was determined by immunoblotting (n = 282). Tumors were categorized as PRA-H (PR-A/PR-B ≥ 1.2) or PRB-H (PR-A/PR-B ≤ 0.83). RNA was extracted for Ribo-Zero-Seq sequencing to evaluate differentially expressed genes. Subtypes and risk scores were predicted using the PAM50 gene set, the data analyzed using The Cancer Genome Atlas RNA-seq gene analysis and other publicly available gene expression data. Tissue microarrays were performed using paraffin-embedded tissues (PRA-H n = 53, PRB-H n = 24), and protein expression analyzed by immunohistochemistry. All statistical tests were two-sided.
  
  
  
  One hundred sixteen out of 222 (52.3%) PR+ tumors were PRA-H, and 64 (28.8%) PRB-H. Cell proliferation was inhibited by MFP in 19 of 19 tissue cultures from PRA-H tumors. A total of 139 transcripts related to proliferative pathways were differentially expressed in nine PRA-H and seven PRB-H tumors. PRB-H and PRA-H tumors were either luminal B or A phenotypes, respectively ( P = .03). PRB-H cases were associated with shorter relapse-free survival (hazard ratio [HR] = 2.70, 95% confidence interval [CI] = 1.71 to 6.20, P = .02) and distant metastasis-free survival (HR = 4.17, 95% CI = 2.18 to 7.97, P <  .001). PRB-H tumors showed increased tumor size ( P <  .001), Ki-67 levels ( P <  .001), human epidermal growth factor receptor 2 expression ( P =  .04), high grades ( P =  .03), and decreased total PR ( P =  .004) compared with PRA-H tumors. MUC-2 ( P <  .001) and KRT6A ( P =  .02) were also overexpressed in PRB-H tumors.
  
  
  
  The PRA/PRB ratio is a prognostic and predictive factor for antiprogestin responsiveness in breast cancer.
authors.affiliation: Laboratory of Hormonal Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
authors.forename: Paola A
authors.initials: PA
authors.lastname: Rojas
authors.affiliation: Laboratory of Hormonal Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
authors.forename: María
authors.initials: M
authors.lastname: May
authors.affiliation: Laboratory of Hormonal Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
authors.forename: Gonzalo R
authors.initials: GR
authors.lastname: Sequeira
authors.affiliation: Laboratory of Hormonal Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
authors.forename: Andrés
authors.initials: A
authors.lastname: Elia
authors.affiliation: Laboratory of Hormonal Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
authors.forename: Michelle
authors.initials: M
authors.lastname: Alvarez
authors.affiliation: Hospital de Agudos Magdalena V de Martínez, General Pacheco, Buenos Aires, Argentina.
authors.forename: Paula
authors.initials: P
authors.lastname: Martínez
authors.affiliation: Hospital de Agudos Magdalena V de Martínez, General Pacheco, Buenos Aires, Argentina.
authors.forename: Pedro
authors.initials: P
authors.lastname: Gonzalez
authors.affiliation: Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Hewitt
authors.affiliation: Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Xiaping
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.affiliation: Moores Cancer Center, University of California, San Diego, CA, USA.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Molinolo
authors.affiliation: Instituto de Efectividad Clínica y Sanitaria, Buenos Aires, Argentina.
authors.forename: Luz
authors.initials: L
authors.lastname: Gibbons
authors.affiliation: CINIBA-CONICET, Escuela de Ciencias Médicas, UNLP, La Plata, Argentina.
authors.forename: Martin C
authors.initials: MC
authors.lastname: Abba
authors.affiliation: Hospital de Agudos Magdalena V de Martínez, General Pacheco, Buenos Aires, Argentina.
authors.forename: Hugo
authors.initials: H
authors.lastname: Gass
authors.affiliation: Laboratory of Hormonal Carcinogenesis, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
authors.forename: Claudia
authors.initials: C
authors.lastname: Lanari
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006727:Hormone Antagonists / Q000627:therapeutic use; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008875:Middle Aged; D015735:Mifepristone / Q000627:therapeutic use*; D020411:Oligonucleotide Array Sequence Analysis; D011237:Predictive Value of Tests; D011372:Progestins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011379:Prognosis; D011980:Receptors, Progesterone / Q000378:metabolism*; D046888:Tissue Array Analysis; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D006727:Hormone Antagonists; D011372:Progestins; D011980:Receptors, Progesterone; C101118:progesterone receptor A; C097314:progesterone receptor B; D015735:Mifepristone