Fibronectin rescues estrogen receptor α from lysosomal degradation in breast cancer cells.
Fibronectin rescues estrogen receptor α from lysosomal degradation in breast cancer cells.
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DOI：
10.1083/jcb.201703037
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发表时间：
2018-08-06
期刊：
影响因子：
--
通讯作者：
Simian M
中科院分区：
文献类型：
--
作者：
Sampayo RG;Toscani AM;Rubashkin MG;Thi K;Masullo LA;Violi IL;Lakins JN;Cáceres A;Hines WC;Coluccio Leskow F;Stefani FD;Chialvo DR;Bissell MJ;Weaver VM;Simian M
在ERα阳性乳腺癌中，约有一半对内分泌治疗无效，这种耐药的原因尚不清楚。Sampayo等表明纤连蛋白（FN）影响ERα阳性囊泡的运输。FN促进ERα定位于Rab 11+囊泡中，拯救ERα免于溶酶体降解，并加强ERα向细胞核的运输和肿瘤细胞中的转录活性。雌激素受体α（ERα）在脑和乳腺等多种组织中表达。在乳腺癌中，ERα是肿瘤进展的关键调节因子。因此，了解是什么激活ERα对于癌症治疗特别是细胞生物学至关重要。使用生物化学方法和超分辨率显微镜，我们发现雌激素驱动膜ERα进入乳腺癌细胞的内体，其命运由细胞外基质中纤连蛋白（FN）的存在决定;在不存在FN的情况下，它被运输到溶酶体，并在其存在时避开溶酶体区室。在这种情况下，FN α的半衰期和增强其转录活性。我们发现ERα与β1-整合素在细胞膜上结合，并且这种整合素遵循相同的由雌激素触发的内吞和亚细胞运输途径。此外，ERα+囊泡存在于人乳腺组织中，并且主要在肿瘤中检测到与β1-整联蛋白的共定位。我们的工作揭示了ERα信号微环境调节的一个关键的临床相关机制。
Among ERα-positive breast cancers, approximately half fail to respond to endocrine therapy, and the causes of this resistance are unknown. Sampayo et al. show that fibronectin (FN) influences the trafficking of ERα-positive vesicles. FN promotes ERα localization in Rab11+ vesicles, rescues ERα from lysosomal degradation, and reinforces ERα trafficking to the nucleus and transcriptional activity in tumor cells. Estrogen receptor α (ERα) is expressed in tissues as diverse as brains and mammary glands. In breast cancer, ERα is a key regulator of tumor progression. Therefore, understanding what activates ERα is critical for cancer treatment in particular and cell biology in general. Using biochemical approaches and superresolution microscopy, we show that estrogen drives membrane ERα into endosomes in breast cancer cells and that its fate is determined by the presence of fibronectin (FN) in the extracellular matrix; it is trafficked to lysosomes in the absence of FN and avoids the lysosomal compartment in its presence. In this context, FN prolongs ERα half-life and strengthens its transcriptional activity. We show that ERα is associated with β1-integrin at the membrane, and this integrin follows the same endocytosis and subcellular trafficking pathway triggered by estrogen. Moreover, ERα+ vesicles are present within human breast tissues, and colocalization with β1-integrin is detected primarily in tumors. Our work unravels a key, clinically relevant mechanism of microenvironmental regulation of ERα signaling.
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影响因子：
24.3
作者：
Correia, Ana Luisa;Bissell, Mina J.
通讯作者：
Bissell, Mina J.
DOI：
10.1111/j.1600-0854.2012.01327.x
发表时间：
2012-04
期刊：
Traffic (Copenhagen, Denmark)
影响因子：
--
作者：
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通讯作者：
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4
作者：
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通讯作者：
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影响因子：
56.9
作者：
Bates, Mark;Huang, Bo;Zhuang, Xiaowei
通讯作者：
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影响因子：
4.8
作者：
Debnath, J;Muthuswamy, SK;Brugge, JS
通讯作者：
Brugge, JS