Department of Mathematics, University of Manitoba, Winnipeg, Canada.
Department of Biology, University of Winnipeg, Winnipeg, Manitoba, Canada.
Sci Rep. 2018 Aug 28;8(1):12969. doi: 10.1038/s41598-018-30447-0.
Breast cancer is the most common cancer in women worldwide. Hormone receptor breast cancers are the most common ones and, about 2 out of every 3 cases of breast cancer are estrogen receptor (ER) positive. Selective ER modulators, such as tamoxifen, are the first line of endocrine treatment of breast cancer. Despite the expression of hormone receptors some patients develop tamoxifen resistance and 50% present de novo tamoxifen resistance. Recently, we have demonstrated that activated mammalian target of rapamycin (mTOR) is positively associated with overall survival and recurrence free survival in ER positive breast cancer patients who were later treated with tamoxifen. Since altered expression of protein kinase B (PKB)/Akt in breast cancer cells affect N-myristoyltransferase 1 (NMT1) expression and activity, we investigated whether mTOR, a downstream target of PKB/Akt, regulates NMT1 in ER positive breast cancer cells (MCF7 cells). We inhibited mTOR by treating MCF7 cells with rapamycin and observed that the expression of NMT1 increased with rapamycin treatment over the period of time with a concomitant decrease in mTOR phosphorylation. We further employed mathematical modelling to investigate hitherto not known relationship of mTOR with NMT1. We report here for the first time a collection of models and data validating regulation of NMT1 by mTOR.
乳腺癌是全世界女性最常见的癌症。激素受体乳腺癌是最常见的一种，大约每 3 例乳腺癌中就有 2 例雌激素受体（ER）阳性。选择性雌激素受体调节剂，如他莫昔芬，是乳腺癌内分泌治疗的一线药物。尽管表达了激素受体，但一些患者仍会产生他莫昔芬耐药性，其中 50%的患者存在原发性他莫昔芬耐药性。最近，我们已经证明，在接受他莫昔芬治疗的 ER 阳性乳腺癌患者中，激活的哺乳动物雷帕霉素靶蛋白（mTOR）与总生存期和无复发生存期呈正相关。由于蛋白激酶 B（PKB/Akt）在乳腺癌细胞中的表达改变会影响 N-豆蔻酰转移酶 1（NMT1）的表达和活性，我们研究了 PKB/Akt 的下游靶点 mTOR 是否调节 ER 阳性乳腺癌细胞（MCF7 细胞）中的 NMT1。我们用雷帕霉素处理 MCF7 细胞来抑制 mTOR，结果发现 NMT1 的表达随着雷帕霉素处理时间的延长而增加，同时 mTOR 磷酸化减少。我们进一步采用数学建模来研究 mTOR 与 NMT1 之间以前未知的关系。我们首次报告了一组模型和数据，验证了 mTOR 对 NMT1 的调节作用。
