Lobular carcinoma in situ and invasive lobular breast cancer are characterized by enhanced expression of transcription factor AP-2β
Lobular carcinoma in situ and invasive lobular breast cancer are characterized by enhanced expression of transcription factor AP-2β
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DOI：
10.1038/labinvest.2017.106
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发表时间：
2018-01-01
影响因子：
5
通讯作者：
Christgen, Matthias
中科院分区：
文献类型：
--
作者：
Raap, Mieke;Gronewold, Malte;Christgen, Matthias
转录因子AP-2β(TFAP2B)调节胚胎器官发育，在一种罕见的儿童恶性肿瘤--泡状横纹肌肉瘤中过度表达。基因表达谱显示AP-2β与乳腺癌(BC)有关。本研究的特点是AP-2β在乳腺和BC中的表达。AP-2β蛋白在正常乳腺上皮、各种反应性、化生性和侵袭性癌前病变中的表达以及在包括2000名患者的两个临床BC队列中的表达被评估。对不同基因工程小鼠(GEM)模型的骨髓细胞也进行了评估。以人BC细胞系为功能模型，研究siRNA对AP-2β的抑制作用。正常乳腺上皮在管腔细胞层可见散在的AP-2β阳性细胞。各种反应性和浸润性癌前病变，包括大汗腺化生、导管常见性增生和小叶原位癌，AP-2β表达增强。导管原位癌中AP-2β表达阴性的例数较多(P<；0.001)。在侵袭性BC队列中，AP-2β阳性与小叶BC亚型(P<；0.001)、E-钙粘附素丢失(PO0.001)、雌激素受体(ER)阳性状态(PO0.001)、低Ki67(P<；0.001)、低/中肿瘤型DX复发评分(PO0.001)以及延长无事件生存期(P=0.003)相关。GEM模型的BCs均为AP-2β阴性。在人BC细胞系中，AP-2β的表达不依赖于ER信号。SiRNA介导的AP-2β抑制可抑制小叶BC细胞系的体外增殖。综上所述，AP-2β是一种新的乳腺上皮分化标志物。其在LC IS和侵袭性小叶性BC中的表达优先保留和增强，并具有预后意义。我们的发现表明，AP-2β控制了这种生长缓慢的BC亚型的肿瘤细胞增殖。
Transcription factor AP-2 beta (TFAP2B) regulates embryonic organ development and is overexpressed in alveolar rhabdomyosarcoma, a rare childhood malignancy. Gene expression profiling has implicated AP-2 beta in breast cancer (BC). This study characterizes AP-2 beta expression in the mammary gland and in BC. AP-2 beta protein expression was assessed in the normal mammary gland epithelium, in various reactive, metaplastic and pre-invasive neoplastic lesions and in two clinical BC cohorts comprising >2000 patients. BCs from various genetically engineered mouse (GEM) models were also evaluated. Human BC cell lines served as functional models to study siRNA-mediated inhibition of AP-2 beta. The normal mammary gland epithelium showed scattered AP-2 beta-positive cells in the luminal cell layer. Various reactive and pre-invasive neoplastic lesions, including apocrine metaplasia, usual ductal hyperplasia and lobular carcinoma in situ (LCIS) showed enhanced AP-2 beta expression. Cases of ductal carcinoma in situ (DCIS) were more often AP-2 beta-negative (P < 0.001). In invasive BC cohorts, AP-2 beta-positivity was associated with the lobular BC subtype (P < 0.001), loss of E-cadherin (Po0.001), a positive estrogen receptor (ER) status (Po0.001), low Ki67 (P < 0.001), low/intermediate Oncotype DX recurrence scores (Po0.001), and prolonged event-free survival (P = 0.003). BCs from GEM models were all AP-2 beta-negative. In human BC cell lines, AP-2 beta expression was independent from ER-signaling. SiRNA-mediated inhibition of AP-2 beta diminished proliferation of lobular BC cell lines in vitro. In summary, AP-2 beta is a new mammary epithelial differentiation marker. Its expression is preferentially retained and enhanced in LCIS and invasive lobular BC and has prognostic implications. Our findings indicate that AP-2 beta controls tumor cell proliferation in this slow-growing BC subtype.