Cytoplasmic PELP1 and ERRgamma protect human mammary epithelial cells from Tam-induced cell death.
Cytoplasmic PELP1 and ERRgamma protect human mammary epithelial cells from Tam-induced cell death.
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DOI：
10.1371/journal.pone.0121206
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Ostrander JH
中科院分区：
文献类型：
--
作者：
Girard BJ;Regan Anderson TM;Welch SL;Nicely J;Seewaldt VL;Ostrander JH
他莫昔芬()是FDA批准的唯一一种针对绝经前乳腺癌高危女性的化学预防药物。虽然降低了女性患雌激素受体阳性(ER+)乳腺癌的风险，但与降低风险相关的分子机制尚不清楚。以往的研究表明，细胞质中的脯氨酸、谷氨酸和亮氨酸富含蛋白1(PELP1)促进乳腺癌细胞株对的耐药。在这里，我们测试了PELP1在乳腺癌高危女性乳腺上皮细胞中的定位，发现PELP1在36%的样本中定位于细胞质。在体外，表达PELP1核定位信号突变体(PELP1-cyto)的永生化人脐静脉内皮细胞对诱导的死亡具有抵抗力。此外，在在场的情况下，通过雌激素相关受体γ(ERRγ)传递的PELP1-细胞信号促进了细胞的存活。ERRγ在永生化HMECs中的过表达对诱导的细胞死亡有保护作用，而ERRγ的敲除使表达PELP1Cyto的HMECs对致敏。此外，诱导的人脐静脉内皮细胞死亡不依赖于细胞凋亡，而是与自噬标志物Lc3-II积聚有关。PELP1Cyto和Errγ的表达减少了诱导的Lc3-II的积聚，而Errγ的敲除使Lc3-II的水平升高作为的反应。此外，PELP1-cyto的表达导致已知的PELP1和Errγ靶基因MMP3和MAOB的表达上调。我们的数据表明，在的存在下，细胞质中的PELP1诱导了聚集在ERRγ上的信号通路，以促进细胞存活。这些数据表明，PELP1的定位和/或ERRγ的激活可以作为反应的组织生物标志物。
Tamoxifen (Tam) is the only FDA-approved chemoprevention agent for pre-menopausal women at high risk for developing breast cancer. While Tam reduces a woman's risk of developing estrogen receptor positive (ER+) breast cancer, the molecular mechanisms associated with risk reduction are poorly understood. Prior studies have shown that cytoplasmic proline, glutamic acid and leucine rich protein 1 (PELP1) promotes Tam resistance in breast cancer cell lines. Herein, we tested for PELP1 localization in breast epithelial cells from women at high risk for developing breast cancer and found that PELP1 was localized to the cytoplasm in 36% of samples. In vitro, immortalized HMECs expressing a nuclear localization signal (NLS) mutant of PELP1 (PELP1-cyto) were resistant to Tam-induced death. Furthermore, PELP1-cyto signaling through estrogen-related receptor gamma (ERRγ) promoted cell survival in the presence of Tam. Overexpression of ERRγ in immortalized HMECs protected cells from Tam-induced death, while knockdown of ERRγ sensitized PELP1-cyto expressing HMECs to Tam. Moreover, Tam-induced HMEC cell death was independent of apoptosis and involved accumulation of the autophagy marker LC3-II. Expression of PELP1-cyto and ERRγ reduced Tam-induced LC3-II accumulation, and knockdown of ERRγ increased LC3-II levels in response to Tam. Additionally, PELP1-cyto expression led to the upregulation of MMP-3 and MAOB, known PELP1 and ERRγ target genes, respectively. Our data indicate that cytoplasmic PELP1 induces signaling pathways that converge on ERRγ to promote cell survival in the presence of Tam. These data suggest that PELP1 localization and/or ERRγ activation could be developed as tissue biomarkers for Tam responsiveness.
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影响因子：
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