Ciblage thérapeutique de la voie Hippo pour le traitement des cancers mammaires chez la chienne
Canine mammary tumors are the most common neoplasms in intact female dogs with 50% of them being malignant tumours. Resection is the standard treatment for canine mammary tumours, but in inoperable cases such as inflammatory carcinomas and advanced metastatic tumours, no efficient chemotherapeutic treatment is available. Studying canine mammary tumour pathogenesis helps with the discovery of novel therapeutic targets and of drugs able to act on these targets to treat the cancer. Recent insight on the Hippo pathway deregulation and the role it plays in breast cancer tumorigenesis, as well as its presence in canine mammary tumours, has lead to our research for the validation of this pathway as a pharmacological target for the treatment of canine mammary gland tumors. Six canine mammary tumour cell lines were assessed for their basal 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 had detectable baseline levels of 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 cell lines that did not have detectable levels of YAP (CF-35, CMT-84) were an order of magnitude more resistant to verteporfin. Verteporfin suppressed the expression of YAP and 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 canine mammary tumour cells. These results will serve as the basis for the development of novel chemotherapeutic approaches for canine mammary tumors that could translate to human medicine.
Verteporfin Mammary gland tumors Dog Hippo pathway Targeted chemotherapy