Department of Clinical and Experimental Medicine, and Department of Oncology, Linköping University, Linköping, Sweden.
Department of Biology, Yeshiva University, New York, NY, USA.
Breast Cancer Res Treat. 2018 Feb;168(1):17-27. doi: 10.1007/s10549-017-4508-x. Epub 2017 Nov 11.
Deregulated PI3K/mTOR signals can promote the growth of breast cancer and contribute to endocrine treatment resistance. This report aims to investigate raptor and its intracellular localization to further understand its role in ER-positive breast cancer.
Raptor protein expression was evaluated by immunohistochemistry in 756 primary breast tumors from postmenopausal patients randomized to tamoxifen or no tamoxifen. In vitro, the MCF7 breast cancer cell line and tamoxifen-resistant MCF7 cells were studied to track the raptor signaling changes upon resistance, and raptor localization in ERα-positive cell lines was compared with that in ERα-negative cell lines.
Raptor protein expression in the nucleus was high in ER/PgR-positive and HER2-negative tumors with low grade, features associated with the luminal A subtype. Presence of raptor in the nucleus was connected with ERα signaling, here shown by a coupled increase of ERα phosphorylation at S167 and S305 with accumulation of nuclear raptor. In addition, the expression of ERα-activated gene products correlated with nuclear raptor. Similarly, in vitro we observed raptor in the nucleus of ERα-positive, but not of ER-negative cells. Interestingly, raptor localized to the nucleus could still be seen in tamoxifen-resistant MCF7 cells. The clinical benefit from tamoxifen was inversely associated with an increase of nuclear raptor. High cytoplasmic raptor expression indicated worse prognosis on long-term follow-up.
We present a connection between raptor localization to the nucleus and ERα-positive breast cancer, suggesting raptor as a player in stimulating the growth of the luminal A subtype and a possible target along with endocrine treatment.
失调的 PI3K/mTOR 信号可促进乳腺癌的生长，并导致内分泌治疗耐药。本报告旨在研究雷帕霉素靶蛋白（Raptor）及其细胞内定位，以进一步了解其在 ER 阳性乳腺癌中的作用。
对 756 例绝经后接受他莫昔芬或不接受他莫昔芬治疗的患者的原发性乳腺癌组织进行 Raptor 蛋白免疫组化评估。体外研究 MCF7 乳腺癌细胞系和他莫昔芬耐药 MCF7 细胞，以跟踪耐药时 Raptor 信号的变化，并比较 ERα阳性细胞系和 ERα阴性细胞系中 Raptor 的定位。
细胞核中 Raptor 蛋白表达高的患者，其肿瘤具有 ER/PgR 阳性、HER2 阴性、低分级等特征，与 luminal A 型相关。细胞核中 Raptor 的存在与 ERα 信号相关，表现为 ERα 磷酸化 S167 和 S305 增加，与核 Raptor 积累相关。此外，ERα 激活基因产物的表达与核 Raptor 相关。同样，我们在体外观察到 ERα 阳性而 ERα 阴性细胞中 Raptor 在细胞核中。有趣的是，在他莫昔芬耐药的 MCF7 细胞中仍可见 Raptor 定位于细胞核。从他莫昔芬治疗中获益与核 Raptor 增加呈负相关。高细胞质 Raptor 表达预示着长期随访的预后较差。
我们提出了 Raptor 定位于细胞核与 ERα 阳性乳腺癌之间的联系，表明 Raptor 可能是刺激 luminal A 型生长的一个因素，可能成为内分泌治疗的一个靶点。
