National Institute of Biomedical Genomics, P.O.: N.S.S., Kalyani, 741251, West Bengal, India.
Tata Memorial Centre/Hospital, Parel, Mumbai, 400012, India.
Breast Cancer Res Treat. 2018 Jul;170(2):431-438. doi: 10.1007/s10549-018-4749-3. Epub 2018 Mar 21.
We have reported a survival benefit of single injection of hydroxyprogesterone prior to surgery for primary tumour in patients with node-positive operable breast cancer. Hydroxyprogesterone was meant to recapitulate the luteal phase of menstrual cycle in these women. We wanted to understand the molecular basis of action of hydroxyprogesterone on primary breast tumours in a peri-operative setting.
We performed whole transcriptome sequencing (RNA-Seq) of primary breast tumour samples collected from patients before and after hydroxyprogesterone exposure and controls. Paired breast cancer samples were obtained from patients who were given hydroxyprogesterone before surgery and a group of patients who were subjected to only surgery.
A test of significance between the two groups revealed 207 significantly altered genes, after correction for multiple hypothesis testing. We found significantly contrasting gene expression patterns in exposed versus unexposed groups; 142 genes were up-regulated post-surgery among exposed patients, and down-regulated post-surgery among unexposed patients. Significantly enriched pathways included genes that respond to progesterone, cellular stress, nonsense-mediated decay of proteins and negative regulation of inflammatory response. These results suggest that cellular stress is modulated by hydroxyprogesterone. Network analysis revealed that UBC, a mediator of stress response, to be a major node to which many of the significantly altered genes connect.
Our study suggests that pre-operative exposure to progesterone favourably modulates the effect of surgical stress, and this might underlie its beneficial effect when administered prior to surgery.
我们曾报道过，在可手术的淋巴结阳性乳腺癌患者中，于术前单次注射羟孕酮可带来生存获益。羟孕酮旨在模拟这些女性月经周期的黄体期。我们希望了解羟孕酮在围手术期对原发性乳腺癌的作用的分子基础。
我们对接受羟孕酮暴露前后的患者和对照组的原发性乳腺癌样本进行了全转录组测序（RNA-Seq）。从接受羟孕酮治疗的患者和仅接受手术的患者中获得配对的乳腺癌样本。
对两组之间的显著性检验发现，经过多重假设检验校正后，有 207 个基因显著改变。我们发现暴露组与未暴露组之间的基因表达模式存在显著差异；暴露组的 142 个基因在手术后上调，而未暴露组的 142 个基因在手术后下调。显著富集的途径包括对孕激素、细胞应激、蛋白质无意义介导的衰变和炎症反应的负调控有反应的基因。这些结果表明，羟孕酮调节细胞应激。网络分析显示，UBC 是应激反应的一个主要节点，许多显著改变的基因与之相连。
我们的研究表明，术前暴露于孕激素可有利地调节手术应激的影响，这可能是其在术前给药时具有有益作用的基础。
