Zymogen granule protein 16B (ZG16B) is a druggable epigenetic target to modulate the mammary extracellular matrix.

IF 5.7 2区 医学 Q1 Medicine
Cancer Science Pub Date : 2024-11-03 DOI:10.1111/cas.16382
Máté Lengyel, Ádám Molnár, Tamás Nagy, Sham Jdeed, Ildikó Garai, Zsolt Horváth, Iván P Uray
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Abstract

High tissue density of the mammary gland is considered a pro-tumorigenic factor, hence suppressing the stimuli that induce matrix buildup carries the potential for cancer interception. We found that in non-malignant mammary epithelial cells the combination of the chemopreventive agents bexarotene (Bex) and carvedilol (Carv) suppresses the zymogen granule protein 16B (ZG16B, PAUF) through an interaction of ARID1A with a proximal enhancer. Bex + Carv also reduced ZG16B levels in vivo in normal breast tissue and MDA-MB231 tumor xenografts. The relevance of ZG16B is underscored by ongoing clinical trials targeting ZG16B in pancreatic cancers, but its role in breast cancer development is unclear. In immortalized mammary epithelial cells, secreted recombinant ZG16B stimulated mitogenic kinase phosphorylation, detachment and mesenchymal characteristics, and promoted proliferation, motility and clonogenic growth. Highly concerted induction of specific laminin, collagen and integrin isoforms indicated a shift in matrix properties toward increased density and cell-matrix interactions. Exogenous ZG16B alone blocked Bex + Carv-mediated control of cell growth and migration, and antagonized Bex + Carv-induced gene programs regulating cell adhesion and migration. In breast cancer cells ZG16B induced colony formation and anchorage-independent growth, and stimulated migration in a PI3K/Akt-dependent manner. In contrast, Bex + Carv inhibited colony formation, reduced Ki67 levels, ZG16B expression and glucose uptake in MDA-MB231 xenografts. These data establish ZG16B as a druggable pro-tumorigenic target in breast cell transformation and suggest a key role of the matrisome network in rexinoid-dependent antitumor activity.

酵母颗粒蛋白16B(ZG16B)是一种可用于调节乳腺细胞外基质的药物表观遗传靶标。
乳腺组织的高密度被认为是一种致癌因素,因此抑制诱导基质堆积的刺激物具有抑制癌症的潜力。我们发现,在非恶性乳腺上皮细胞中,化学预防剂贝沙罗汀(Bex)和卡维地洛(Carv)的组合能通过 ARID1A 与近端增强子的相互作用抑制酶原颗粒蛋白 16B(ZG16B,PAUF)。Bex + Carv 还降低了正常乳腺组织和 MDA-MB231 肿瘤异种移植体内的 ZG16B 水平。正在进行的针对胰腺癌的临床试验强调了 ZG16B 的相关性,但它在乳腺癌发展中的作用尚不清楚。在永生化乳腺上皮细胞中,分泌的重组 ZG16B 可刺激有丝分裂激酶磷酸化、脱落和间质特征,并促进增殖、运动和克隆性生长。对特定层粘蛋白、胶原蛋白和整合素同工酶的高度协同诱导表明,基质特性向密度增加和细胞-基质相互作用转变。单用外源 ZG16B 可阻断 Bex + Carv 介导的细胞生长和迁移控制,并拮抗 Bex + Carv 诱导的细胞粘附和迁移基因程序。在乳腺癌细胞中,ZG16B 以 PI3K/Akt 依赖性方式诱导集落形成和不依赖锚定的生长,并刺激迁移。与此相反,Bex + Carv 可抑制 MDA-MB231 异种移植中的集落形成,降低 Ki67 水平、ZG16B 表达和葡萄糖摄取。这些数据确立了 ZG16B 在乳腺细胞转化过程中是一个可药用的致癌靶点,并表明母体网络在雷公藤依赖性抗肿瘤活性中发挥着关键作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cancer Science
Cancer Science ONCOLOGY-
CiteScore
9.90
自引率
3.50%
发文量
406
审稿时长
17 weeks
期刊介绍: Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.
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