Loss of c-Jun NH2-Terminal Kinase in Mammary Epithelial Cells is Sufficient for Adenosquamous Tumor Formation

The JNK pathway has been implicated in breast cancer, both from human tumor sequencing studies and from mouse models. To see if JNK deletion is able to form tumors in mice, we crossed Mapk8 and Mapk9 conditional animals with the WAP-Cre expressing mouse to specifically delete JNK in luminal epithelial cells of the breast. We found that JNK suppresses tumors and that the loss of JNK leads to adenosquamous carcinoma formation. To understand the role of JNK in the mammary epithelium, we performed RNA sequencing and analyzed gene expression from tumor-derived cell lines. Several pathways were perturbed in the carcinoma cell lines. Our results demonstrate that loss of JNK alone is sufficient to cause tumor formation and they reveal a gene signature of adenosquamous tumors that can help in better understanding and treating the disease. Mammary epithelial cell (control) and adenosquamous tumor cell line expression was analyzed using three independent libraries of each

JNK信号通路（JNK pathway）已被多项人类肿瘤测序研究及小鼠模型研究证实与乳腺癌密切相关。为验证JNK缺失是否可诱导小鼠体内肿瘤生成，我们将丝裂原活化蛋白激酶8（Mapk8）与丝裂原活化蛋白激酶9（Mapk9）条件性基因敲除小鼠与表达WAP-Cre的小鼠进行杂交，以特异性敲除小鼠乳腺腔上皮细胞中的JNK。实验结果显示，JNK可抑制肿瘤发生，而JNK缺失会诱导腺鳞癌的形成。为探究JNK在乳腺上皮中的功能，我们对肿瘤来源的细胞系进行了RNA测序（RNA sequencing）并分析其基因表达情况。腺鳞癌细胞系中存在多条信号通路的紊乱。本研究结果证实，仅JNK缺失即可诱导肿瘤生成，同时还揭示了腺鳞癌的基因特征谱，这将有助于加深对该疾病的理解并优化临床治疗策略。本研究针对乳腺上皮细胞（对照组）与腺鳞癌细胞系的基因表达水平进行分析，每组均设置3个独立测序文库。