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Progesterone Receptor Isoform Ratio: A Breast Cancer Prognostic and Predictive Factor for Antiprogestin Responsiveness.
- Source :
- JNCI: Journal of the National Cancer Institute; Jul2017, Vol. 109 Issue 7, p1-9, 9p
- Publication Year :
- 2017
-
Abstract
- <bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusion: </bold>The PRA/PRB ratio is a prognostic and predictive factor for antiprogestin responsiveness in breast cancer. [ABSTRACT FROM AUTHOR]
- Subjects :
- PROGESTERONE receptors
BREAST cancer
IMMUNOBLOTTING
IMMUNOASSAY
CHEST (Anatomy)
MIFEPRISTONE
HORMONE antagonists
BREAST tumors
CELL physiology
CELL receptors
GENES
IMMUNOHISTOCHEMISTRY
PROGESTATIONAL hormones
PROGNOSIS
TREATMENT effectiveness
PREDICTIVE tests
OLIGONUCLEOTIDE arrays
TISSUE arrays
GENE expression profiling
CANCER cell culture
CHEMICAL inhibitors
THERAPEUTICS
Subjects
Details
- Language :
- English
- ISSN :
- 00278874
- Volume :
- 109
- Issue :
- 7
- Database :
- Complementary Index
- Journal :
- JNCI: Journal of the National Cancer Institute
- Publication Type :
- Academic Journal
- Accession number :
- 124181392
- Full Text :
- https://doi.org/10.1093/jnci/djw317