Lengyel Máté, Molnár Ádám, Nagy Tamás, Jdeed Sham, Garai Ildikó, Horváth Zsolt, Uray Iván P
Department of Clinical Oncology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
The Molecular Cell and Immune Biology Doctoral School, University of Debrecen, Debrecen, Hungary.
Cancer Sci. 2025 Jan;116(1):81-94. doi: 10.1111/cas.16382. Epub 2024 Nov 3.
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.
乳腺组织密度高被认为是一种促肿瘤发生因素，因此抑制诱导基质积累的刺激因素具有癌症拦截的潜力。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中ZG16B的临床试验强调了ZG16B的相关性，但其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刺激有丝分裂激酶磷酸化、细胞脱离和间充质特征，并促进增殖、运动和克隆生长。特定层粘连蛋白、胶原蛋白和整合素亚型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。单独的外源性ZG16B阻断了Bex + Carv介导的细胞生长和迁移控制，并拮抗了Bex + Carv诱导的调节细胞粘附和迁移的基因程序。在乳腺癌细胞中，ZG16B诱导集落形成和不依赖贴壁生长，并以PI3K/Akt依赖的方式刺激迁移。相比之下，Bex + Carv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。这些数据确定ZG16B是乳腺细胞转化中可成药的促肿瘤发生靶点，并表明基质网络在视黄酸依赖性抗肿瘤活性中的关键作用。
