Decreased expression of Yes-associated protein is associated with outcome in the luminal A breast cancer subgroup and with an impaired tamoxifen response.
Decreased expression of Yes-associated protein is associated with outcome in the luminal A breast cancer subgroup and with an impaired tamoxifen response.
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DOI：
10.1186/1471-2407-14-119
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发表时间：
2014-02-22
期刊：
影响因子：
3.8
通讯作者：
Landberg G
中科院分区：
文献类型：
--
作者：
Lehn S;Tobin NP;Sims AH;Stål O;Jirström K;Axelson H;Landberg G
YAP 1是一种常见的癌基因，在多种癌症中发挥作用，但在乳腺癌中的结果仍存在争议。我们着手阐明YAP 1在乳腺癌中的作用，通过检查患者材料亚组中的基因和蛋白质表达，并通过下调YAP 1在体外和研究其在广泛使用的抗雌激素他莫昔芬反应中的作用。在两个原发性乳腺癌群组（n = 144和n = 564）中，YAP 1蛋白强度被评分为不存在、弱、中等或强，并且在基因表达数据集中评估YAP 1的mRNA表达（n = 1107）。使用对数秩检验分析无复发生存期，使用考克斯多变量分析检验独立性。采用WST-1测定来测量细胞活力，并使用荧光素酶ERE（雌激素响应元件）构建体来研究在使用siRNA下调YAP 1后他莫昔芬的作用。在随机队列的ER+（雌激素受体α阳性）亚组中，YAP 1表达与组织学分级和增殖呈负相关（分别为p = 0.001和p = 0.016），而在ER-（雌激素受体α阴性）亚组中，YAP 1表达与增殖呈正相关（p = 0.005）。值得注意的是，在基因表达数据集中，低YAP 1 mRNA与降低的无复发生存率独立相关，特别是对于管腔A亚组（p < 0.001），其包括较低级别的低增殖肿瘤，通常与良好的预后相关。这种亚组特异性使我们假设YAP 1可能对内分泌疗法的反应很重要，例如广泛用于管腔A型乳腺癌的他莫昔芬。在他莫昔芬随机化患者材料中，YAP 1蛋白表达缺失与他莫昔芬反应受损相关，这在相互作用分析中是显著的（p = 0.042）。YAP 1下调导致孕酮受体（PgR）表达增加和他莫昔芬延迟和较弱，支持临床数据。在侵袭性较低的管腔A型乳腺癌亚组中，YAP 1表达降低是复发的独立预后因素，这可能是由于YAP 1下调导致他莫昔芬敏感性降低。
Yes-associated protein (YAP1) is frequently reported to function as an oncogene in many types of cancer, but in breast cancer results remain controversial. We set out to clarify the role of YAP1 in breast cancer by examining gene and protein expression in subgroups of patient material and by downregulating YAP1 in vitro and studying its role in response to the widely used anti-estrogen tamoxifen. YAP1 protein intensity was scored as absent, weak, intermediate or strong in two primary breast cancer cohorts (n = 144 and n = 564) and mRNA expression of YAP1 was evaluated in a gene expression dataset (n = 1107). Recurrence-free survival was analysed using the log-rank test and Cox multivariate analysis was used to test for independence. WST-1 assay was employed to measure cell viability and a luciferase ERE (estrogen responsive element) construct was used to study the effect of tamoxifen, following downregulation of YAP1 using siRNAs. In the ER+ (Estrogen Receptor α positive) subgroup of the randomised cohort, YAP1 expression was inversely correlated to histological grade and proliferation (p = 0.001 and p = 0.016, respectively) whereas in the ER- (Estrogen Receptor α negative) subgroup YAP1 expression correlated positively to proliferation (p = 0.005). Notably, low YAP1 mRNA was independently associated with decreased recurrence-free survival in the gene expression dataset, specifically for the luminal A subgroup (p < 0.001) which includes low proliferating tumours of lower grade, usually associated with a good prognosis. This subgroup specificity led us to hypothesize that YAP1 may be important for response to endocrine therapies, such as tamoxifen, extensively used for luminal A breast cancers. In a tamoxifen randomised patient material, absent YAP1 protein expression was associated with impaired tamoxifen response which was significant upon interaction analysis (p = 0.042). YAP1 downregulation resulted in increased progesterone receptor (PgR) expression and a delayed and weaker tamoxifen in support of the clinical data. Decreased YAP1 expression is an independent prognostic factor for recurrence in the less aggressive luminal A breast cancer subgroup, likely due to the decreased tamoxifen sensitivity conferred by YAP1 downregulation.
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影响因子：
3.5
作者：
Gaffney CJ;Oka T;Mazack V;Hilman D;Gat U;Muramatsu T;Inazawa J;Golden A;Carey DJ;Farooq A;Tromp G;Sudol M
通讯作者：
Sudol M
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
11.2
作者：
Helczynska, Karolina;Larsson, Anna-Maria;Jirstrom, Karin
通讯作者：
Jirstrom, Karin
影响因子：
64.5
作者：
Alarcón C;Zaromytidou AI;Xi Q;Gao S;Yu J;Fujisawa S;Barlas A;Miller AN;Manova-Todorova K;Macias MJ;Sapkota G;Pan D;Massagué J
通讯作者：
Massagué J
影响因子：
8
作者：
Ferrigno, O;Lallemand, F;Mauviel, A
通讯作者：
Mauviel, A