Raptor localization predicts prognosis and tamoxifen response in estrogen receptor-positive breast cancer.
Raptor localization predicts prognosis and tamoxifen response in estrogen receptor-positive breast cancer.
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DOI：
10.1007/s10549-017-4508-x
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发表时间：
2018-03
影响因子：
3.8
通讯作者：
Stål O
中科院分区：
文献类型：
--
作者：
Bostner J;Alayev A;Berman AY;Fornander T;Nordenskjöld B;Holz MK;Stål O
PI 3 K/mTOR信号失调可促进乳腺癌的生长，并有助于内分泌治疗抵抗。本报告旨在研究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。采用免疫组织化学方法对756例绝经后原发性乳腺肿瘤患者的Raptor蛋白表达进行了评价，这些患者被随机分为三苯氧胺组和非三苯氧胺组。在体外研究了MCF 7乳腺癌细胞系和他莫昔芬耐药MCF 7细胞，以跟踪raptor信号转导的变化，并比较了raptor在ERα阳性细胞系和ERα阴性细胞系中的定位。Raptor蛋白在ER/PgR阳性和HER 2阴性肿瘤细胞核中的表达较高，具有低级别，与管腔A亚型相关的特征。Raptor在细胞核中的存在与ERα信号传导有关，这里通过在S167和S305处ERα磷酸化的偶联增加与细胞核raptor的积累来显示。此外，ERα激活基因产物的表达与核猛禽有关。同样，在体外我们观察到raptor在ERα阳性细胞的细胞核中，而不是ER阴性细胞。有趣的是，在他莫昔芬耐药的MCF 7细胞中仍然可以看到定位于细胞核的raptor。他莫昔芬的临床获益与核猛禽的增加呈负相关。高胞浆Raptor表达提示长期随访预后较差。我们提出了猛禽定位于细胞核和ERα阳性乳腺癌之间的联系，表明猛禽作为刺激管腔A亚型生长的参与者和内分泌治疗的可能靶点沿着。本文的在线版本（10.1007/s10549-017-4508-x）包含补充材料，可供授权用户使用。
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. The online version of this article (10.1007/s10549-017-4508-x) contains supplementary material, which is available to authorized users.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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