Membrane progesterone receptor alpha as a potential prognostic biomarker for breast cancer survival: a retrospective study

Abstract

Classically, the actions of progesterone (P4) are attributed to the binding of nuclear progesterone receptor (PR) and subsequent activation of its downstream target genes. These mechanisms, however, are not applicable to PR- or basal phenotype breast cancer (BPBC) due to lack of PR in these cancers. Recently, the function of membrane progesterone receptor alpha (mPRα) in human BPBC cell lines was studied in our lab. We proposed that the signaling cascades of P4→mPRα pathway may play an essential role in controlling cell proliferation and epithelial mesenchymal transition (EMT) of breast cancer. Using human breast cancer tissue microarrays, we found in this study that the average intensity of mPRα expression, but not percentage of breast cancer with high level of mPRα expression (mPRα-HiEx), was significantly lower in the TNM stage 4 patients compared to those with TNM 1-3 patients; and both average intensities of mPRα expression and mPRα-HiEx rates were significantly higher in cancers negative for ER, as compared with those cancers with ER+. However, after adjusting for age at diagnosis and/or TNM stage, only average intensities of mPRα expression were associated with ER status. In addition, we found that the rates of mPRα-HiEx were significantly higher in cancers with epithelial growth factor receptor-1 (EGFR+) and high level of Ki67 expression, indicating positive correlation between mPRα over expression and EGFR or Ki67. Further analysis indicated that both mPRα-HiEx rate and average intensity of mPRα expression were significantly higher in HER2+ subtype cancers (i.e. HER2+ER-PR-) as compared to ER+ subtype cancers. These data support our hypothesis that P4 modulates the activities of the PI3K and cell proliferation pathways through the caveolar membrane bound growth factor receptors such as mPRα and growth factor receptors. Future large longitudinal studies with larger sample size and survival outcomes are necessary to confirm our findings.

Figure 1. Immunohistochemical stain intensities of mPRα and controls.

Figure 1A shows the western blot assay of cellular proteins (duplicates) isolated from MB231 and MB231-mPR (mPRα cDNA stably transfected MB231 cells). Figure 1B – 1E show the tissue microarray cores that are negative (1B), weak (1C), moderate (1D), and strong positive (1E). The positive stain signals are indicated as black arrows. Figure 1F shows a benign breast disease core with weak mPR positive stain in epithelium (black arrow) and strong positive stain in myoepithelium (brown arrow). Image was taken a 20× lens.