Membrane progesterone receptor alpha as a potential prognostic biomarker for breast cancer survival: a retrospective study.
Membrane progesterone receptor alpha as a potential prognostic biomarker for breast cancer survival: a retrospective study.
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DOI：
10.1371/journal.pone.0035198
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
You S
中科院分区：
文献类型：
--
作者：
Xie M;Zhu X;Liu Z;Shrubsole M;Varma V;Mayer IA;Dai Q;Chen Q;You S
经典地，孕酮（P4）的作用归因于核孕酮受体（PR）的结合及其下游靶基因的随后激活。然而，这些机制不适用于PR或基础表型乳腺癌（BPBC），因为这些癌症中缺乏PR。本实验室最近对人BPBC细胞膜孕激素受体α（mPRα）的功能进行了研究。提示P4→mPRα信号通路可能在乳腺癌细胞增殖和上皮间质转化（EMT）过程中起重要作用。利用人乳腺癌组织芯片，我们发现在本研究中，mPRα表达的平均强度，而不是乳腺癌中mPRα高表达的百分比，（mPRα-HiEx）在TNM 4期患者中显著低于TNM 1-3期患者; ER阴性组mPRα平均表达强度和mPRα-HiEx阳性率均显著高于ER阳性组。然而，在调整诊断时的年龄和/或TNM分期后，只有mPRα表达的平均强度与ER状态相关。此外，我们发现mPRα-HiEx在上皮生长因子受体-1（EGFR+）和Ki 67高表达的癌症中的比率显著较高，表明mPRα过表达与EGFR或Ki 67正相关。进一步分析表明，与ER+亚型癌症相比，HER 2+亚型癌症（即HER 2 +ER-PR-）中的mPRα-HiEx率和mPRα表达的平均强度均显著更高。这些数据支持了我们的假设，即P4通过膜结合生长因子受体如mPRα和生长因子受体调节PI 3 K和细胞增殖途径的活性。未来需要更大样本量和生存结局的大型纵向研究来证实我们的发现。
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.
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