APRIL promotes breast tumor growth and metastasis and is associated with aggressive basal breast cancer
APRIL promotes breast tumor growth and metastasis and is associated with aggressive basal breast cancer
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DOI：
10.1093/carcin/bgv020
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发表时间：
2015-05-01
期刊：
影响因子：
4.7
通讯作者：
Planelles, Lourdes
中科院分区：
文献类型：
--
作者：
Garcia-Castro, Araceli;Zonca, Manuela;Planelles, Lourdes
APRIL促进乳腺肿瘤的发生和转移。通过细胞系、原位肿瘤模型和原发性乳腺癌样本，我们发现APRIL信号通路与肿瘤细胞侵袭性有关，是乳腺癌治疗的一个有希望的靶点。APRIL（一种增殖诱导配体）是肿瘤坏死因子家族中的一种细胞因子，主要与血液恶性肿瘤相关。APRIL也在乳腺癌组织病变中过度表达，尽管其在乳腺肿瘤发生中的作用和潜在的分子机制都不清楚。在这里，我们发现一些乳腺癌细胞系表达APRIL及其受体，B细胞成熟抗原（BCMA）和跨膜激活因子和caml相互作用因子（TACI），独立于腔内或基底肿瘤细胞表型，并且丝裂原激活的蛋白激酶p38， ERK1/2和JNK1/2在APRIL的响应中被激活。炎症刺激poly I:C， toll样受体（TLR） 3配体，促进APRIL分泌。沉默实验降低了细胞增殖，表明APRIL是乳腺肿瘤生长的关键自分泌因子。在APRIL转基因小鼠中对4T1原位乳腺肿瘤的研究表明，富含APRIL的环境可促进肿瘤生长，促进肺转移，并增强肿瘤细胞增殖；BCMA和TACI的表达表明两者都参与了这些过程。我们在人类腔型乳腺癌、三阴性乳腺癌和HER2乳腺癌中检测到了APRIL、BCMA和TACI，并且在侵袭性更强的基底肿瘤中检测到了升高的水平。APRIL在Ki67（+）核附近可见，并在癌细胞、白细胞浸润及邻近肿瘤区域的肌上皮内分布不均；这些结果表明，APRIL通过旁分泌和自分泌信号向肿瘤细胞提供增殖信号。我们的研究确定了APRIL信号在乳腺癌促进中的参与；我们建议损伤这一通路作为一种潜在的治疗策略。
APRIL promotes breast tumorigenesis and metastasis. Using cell lines, orthotopic tumor models and primary breast carcinoma samples, we show that the APRIL signaling pathway associates with tumor cell aggressiveness and is a promising target for breast cancer therapy.APRIL (a proliferation-inducing ligand) is a cytokine of the tumor necrosis factor family associated mainly with hematologic malignancies. APRIL is also overexpressed in breast carcinoma tissue lesions, although neither its role in breast tumorigenesis nor the underlying molecular mechanism is known. Here, we show that several breast cancer cell lines express APRIL and both its receptors, B cell maturation antigen (BCMA) and transmembrane activator and CAML-interactor (TACI), independently of luminal or basal tumor cell phenotype, and that the mitogen-activated protein kinases p38, ERK1/2, and JNK1/2 are activated in response to APRIL. The inflammatory stimulus poly I:C, a toll-like receptor (TLR) 3 ligand, enhanced APRIL secretion. Silencing experiments decreased cell proliferation, demonstrating that APRIL is a critical autocrine factor for breast tumor growth. Studies of 4T1 orthotopic breast tumors in APRIL transgenic mice showed that an APRIL-enriched environment increased tumor growth and promoted lung metastasis associated with enhanced tumor cell proliferation; BCMA and TACI expression suggests that both participate in these processes. We detected APRIL, BCMA and TACI in human luminal, triple-negative breast carcinomas and HER2 breast carcinomas, with increased levels in more aggressive basal tumors. APRIL was observed near Ki67(+) nuclei and was distributed heterogeneously in the cancer cells, in the leukocyte infiltrate, and in the myoepithelial layer adjacent to the tumor area; these results imply that APRIL provides proliferation signals to tumor cells through paracrine and autocrine signaling. Our study identifies participation of APRIL signaling in breast cancer promotion; we propose impairment of this pathway as a potential therapeutic strategy.