Histopathology core, Atlanta Research & Educational Foundation/Atlanta VA Medical Center, Decatur, Georgia, United States of America.
PLoS One. 2012;7(4):e35198. doi: 10.1371/journal.pone.0035198. Epub 2012 Apr 4.
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.
经典理论认为，孕激素（P4）的作用归因于核孕激素受体（PR）的结合及其下游靶基因的激活。然而，这些机制不适用于 PR 阴性或基底表型乳腺癌（BPBC），因为这些癌症中缺乏 PR。最近，我们实验室研究了人 BPBC 细胞系中膜孕激素受体 alpha（mPRα）的功能。我们提出，P4→mPRα 通路的信号级联可能在控制乳腺癌细胞增殖和上皮间质转化（EMT）中发挥重要作用。使用人乳腺癌组织微阵列，我们在这项研究中发现，与 TNM 分期 1-3 期患者相比，TNM 分期 4 期患者的 mPRα 表达平均强度显著降低，但 mPRα 高表达（mPRα-HiEx）的乳腺癌百分比没有显著降低；ER 阴性的癌症中 mPRα 表达的平均强度和 mPRα-HiEx 率均显著高于 ER 阳性的癌症。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 率在 EGFR 阳性和 Ki67 高表达的癌症中显著较高，表明 mPRα 过表达与 EGFR 或 Ki67 呈正相关。进一步分析表明，与 ER+亚型癌症相比，HER2+亚型癌症（即 HER2+ER-PR-）的 mPRα-HiEx 率和 mPRα 表达平均强度均显著较高。这些数据支持我们的假设，即 P4 通过腔膜结合的生长因子受体（如 mPRα 和生长因子受体）调节 PI3K 和细胞增殖途径的活性。需要进行未来的大型纵向研究，以更大的样本量和生存结果来证实我们的发现。
