Autophagy regulator BECN1 suppresses mammary tumorigenesis driven by WNT1 activation and following parity.
Autophagy regulator BECN1 suppresses mammary tumorigenesis driven by WNT1 activation and following parity.
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DOI：
10.4161/auto.34398
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发表时间：
2014
期刊：
影响因子：
13.3
通讯作者：
Karantza V
中科院分区：
文献类型：
--
作者：
Cicchini M;Chakrabarti R;Kongara S;Price S;Nahar R;Lozy F;Zhong H;Vazquez A;Kang Y;Karantza V
早期的研究报告了乳腺癌中基本的自噬调节因子BECN1的等位基因缺失，这与BECN1缺失有关，而且可能是自噬缺陷，在肿瘤发生中。最近的研究质疑自噬的肿瘤抑制作用，因为自噬相关基因(ATG)缺陷通常会在特征良好的小鼠肿瘤模型中抑制肿瘤发生。我们现在报道，虽然它延缓或不改变由PALB2缺失或ERBB2和PYMT过表达驱动的乳腺肿瘤的发生，但单等位基因Becn1缺失在两个特定的背景下促进乳腺肿瘤的发生，即在产次后和与无翼型MMTV整合位点家族成员1(WNT1)激活有关。我们的研究表明，Becn1杂合性导致未成熟的乳腺上皮细胞扩张和TNFRSF11A/TNR11/RANK(肿瘤坏死因子受体超家族成员11a，NFKB激活子)信号的异常，促进了经产FVB/N小鼠的乳腺肿瘤的发生，并与转化WNT1癌基因的祖细胞协同作用。与我们的Becn1+/−；MMTV-WNT1小鼠模型相似，BECN1的低表达和激活的WNT通路基因信号与人类乳腺癌的三阴性亚型、TNFRSF11A轴激活和预后不良相关。我们的结果表明，BECN1可能在乳腺发育中具有非自噬相关的作用，为深入了解BECN1在肿瘤发生中看似矛盾的作用提供了线索，并为进一步研究临床侵袭性三阴性乳腺癌(TNBCs)的病理生理和治疗奠定了基础。
Earlier studies reported allelic deletion of the essential autophagy regulator BECN1 in breast cancers implicating BECN1 loss, and likely defective autophagy, in tumorigenesis. Recent studies have questioned the tumor suppressive role of autophagy, as autophagy-related gene (Atg) defects generally suppress tumorigenesis in well-characterized mouse tumor models. We now report that, while it delays or does not alter mammary tumorigenesis driven by Palb2 loss or ERBB2 and PyMT overexpression, monoallelic Becn1 loss promotes mammary tumor development in 2 specific contexts, namely following parity and in association with wingless-type MMTV integration site family, member 1 (WNT1) activation. Our studies demonstrate that Becn1 heterozygosity, which results in immature mammary epithelial cell expansion and aberrant TNFRSF11A/TNR11/RANK (tumor necrosis factor receptor superfamily, member 11a, NFKB activator) signaling, promotes mammary tumorigenesis in multiparous FVB/N mice and in cooperation with the progenitor cell-transforming WNT1 oncogene. Similar to our Becn1+/−;MMTV-Wnt1 mouse model, low BECN1 expression and an activated WNT pathway gene signature correlate with the triple-negative subtype, TNFRSF11A axis activation and poor prognosis in human breast cancers. Our results suggest that BECN1 may have nonautophagy-related roles in mammary development, provide insight in the seemingly paradoxical roles of BECN1 in tumorigenesis, and constitute the basis for further studies on the pathophysiology and treatment of clinically aggressive triple negative breast cancers (TNBCs).