Guillemette Samantha, Rico Charlène, Godin Philippe, Boerboom Derek, Paquet Marilène
Département de pathologie et de microbiologie, Faculté de médecine vétérinaire, Université de Montréal, Saint-Hyacinthe, QC, Canada.
Département de Biomédecine Vétérinaire, Faculté de médecine vétérinaire, Université de Montréal, Saint-Hyacinthe, QC, Canada.
J Mammary Gland Biol Neoplasia. 2017 Sep;22(3):203-214. doi: 10.1007/s10911-017-9384-9. Epub 2017 Aug 18.
Canine mammary tumors (CMTs) are the most common neoplasms in intact female dogs. Some clinical and molecular similarities between certain CMT subtypes and breast cancer make them a potential model for the study of the human disease. As misregulated Hippo signaling is thought to play an important role in breast cancer development and also occurs in CMTs, we sought to determine if Hippo represents a valid pharmacological target for the treatment of CMTs. Six CMT cell lines were assessed for their expression of the Hippo pathway effectors YAP and TAZ and for their sensitivity to verteporfin, an inhibitor of YAP-mediated transcriptional coactivation. Four cell lines that expressed YAP (CMT-9, -12, -28, -47) were found to be very sensitive to verteporfin treatment, which killed the cells through induction of apoptosis with ED50 values of 14-79 nM. Conversely, two YAP-negative cell lines (CF-35, CMT-25) were an order of magnitude more resistant to verteporfin. Verteporfin suppressed the expression of YAP/TAZ target genes, particularly CYR61 and CTGF, which play important roles in breast cancer development. Verteporfin was also able to inhibit cell migration and anchorage-independent growth. Likewise, verteporfin efficiently suppressed tumor cell invasiveness in the CMT-28 and -47 lines, but not in CF-35 cells. Together, our findings provide proof of principle that pharmacological targeting of the Hippo pathway compromises the viability and attenuates the malignant behavior of CMT cells. These results will serve as the basis for the development of novel chemotherapeutic approaches for CMTs that could translate to human medicine.
犬乳腺肿瘤（CMTs）是未绝育雌性犬中最常见的肿瘤。某些CMT亚型与乳腺癌之间存在一些临床和分子相似性，这使它们成为研究人类疾病的潜在模型。由于失调的Hippo信号通路被认为在乳腺癌发展中起重要作用，且在CMTs中也存在，我们试图确定Hippo是否是治疗CMTs的有效药理学靶点。评估了六种CMT细胞系中Hippo信号通路效应分子YAP和TAZ的表达，以及它们对维替泊芬（一种YAP介导的转录共激活抑制剂）的敏感性。发现四种表达YAP的细胞系（CMT - 9、- 12、- 28、- 47）对维替泊芬治疗非常敏感，维替泊芬通过诱导细胞凋亡杀死细胞，半数有效浓度（ED50）值为14 - 79 nM。相反，两种YAP阴性细胞系（CF - 35、CMT - 25）对维替泊芬的抗性高一个数量级。维替泊芬抑制YAP/TAZ靶基因的表达，特别是CYR61和CTGF，它们在乳腺癌发展中起重要作用。维替泊芬还能够抑制细胞迁移和不依赖贴壁的生长。同样，维替泊芬有效地抑制了CMT - 28和 - 47细胞系中的肿瘤细胞侵袭，但对CF - 35细胞无效。总之，我们的研究结果提供了原理证明，即对Hippo信号通路进行药理学靶向会损害CMT细胞的活力并减弱其恶性行为。这些结果将为开发可转化至人类医学的CMTs新型化疗方法奠定基础。
