Araiza-Olivera Daniela, Prudnikova Tatiana Y, Uribe-Alvarez Cristina, Cai Kathy Q, Franco-Barraza Janusz, Dones Jesus M, Raines Ronald T, Chernoff Jonathan
Cancer Signaling and Microenvironment Program, Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
Histopathology Facility, Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
Mol Cancer Res. 2025 May 2;23(5):405-415. doi: 10.1158/1541-7786.MCR-24-0331.
Breast cancers of the Integrative Cluster 2 (IntClust-2) type, characterized by amplification of a small portion of chromosome 11, have a median survival of only 5 years. Several cancer-relevant genes occupy this portion of chromosome 11, and it is thought that overexpression of a combination of driver genes in this region is responsible for the poor outcome of women in this group. In this study, we used a gene editing method to knock out, one by one, each of the 198 genes that are located within the amplified region of chromosome 11 and determined how much each of these genes contributed to the survival of breast cancer cells. In addition to well-known drivers such as CCND1 and PAK1, we identified two different genes (SERPINH1 and P4HA3) that encode proteins involved in collagen synthesis and organization. Using both in vitro and in vivo functional analyses, we determined that P4HA3 and/or SERPINH1 provide a critical driver function for IntClust-2 basic processes, such as viability, proliferation, and migration. Inhibiting these enzymes via genetic or pharmacologic means reduced collagen synthesis and impeded oncogenic signaling transduction in cell culture models, and a small-molecule inhibitor of P4HA3 was effective in treating 11q13 tumor growth in an animal model. As collagen has a well-known association with tissue stiffness and aggressive forms of breast cancer, we believe that the two genes we identified provide an opportunity for a new therapeutic strategy in IntClust-2 breast cancers. Implications: Breast cancers with 11q13/14 chromosomal amplifications may be vulnerable to inhibitors of collagen synthesis.
整合簇2（IntClust-2）型乳腺癌，其特征是11号染色体一小部分区域发生扩增，中位生存期仅为5年。几个与癌症相关的基因位于11号染色体的这一区域，人们认为该区域中驱动基因组合的过表达是导致这组女性预后不良的原因。在本研究中，我们采用基因编辑方法逐一敲除位于11号染色体扩增区域内的198个基因，并确定这些基因中每个基因对乳腺癌细胞存活的贡献程度。除了CCND1和PAK1等知名驱动基因外，我们还鉴定出两个不同的基因（SERPINH1和P4HA3），它们编码参与胶原蛋白合成和组织的蛋白质。通过体外和体内功能分析，我们确定P4HA3和/或SERPINH1为IntClust-2的基本过程（如生存能力、增殖和迁移）提供关键的驱动功能。在细胞培养模型中，通过基因或药理学手段抑制这些酶可减少胶原蛋白合成并阻碍致癌信号转导，并且一种P4HA3小分子抑制剂在动物模型中有效治疗11q13肿瘤生长。由于胶原蛋白与组织硬度和侵袭性乳腺癌形式有着众所周知的关联，我们认为我们鉴定出的这两个基因提供了一种针对IntClust-2型乳腺癌的新治疗策略的机会。启示：具有11q13/14染色体扩增的乳腺癌可能对胶原蛋白合成抑制剂敏感。
