Wnt/β-Catenin and Hippo Pathway Deregulation in Mammary Tumors of Humans, Dogs, and Cats

Abstract

Mammary cancer is a common neoplasm in women, dogs, and cats that still represents a therapeutic challenge. Wnt/β-catenin and Hippo pathways are involved in tumor progression, cell differentiation, and metastasis. The aim of this study was to evaluate mRNA and protein expression of molecules involved in these pathways in human (HBC), canine (CMT), and feline mammary tumors (FMT). Real-time quantitative polymerase chain reaction (qPCR) for β-catenin, CCND1, YAP, TAZ, CTGF, and ANKRD1, western blotting for YAP, TAZ, and β-catenin, and immunohistochemistry for estrogen receptor (ER), progesterone receptor (PR), ERBB2, β-catenin, and YAP/TAZ were performed on mammary tumor tissues. The protein expression of active β-catenin was higher in tumors than in healthy tissues in all 3 species. The mRNA expression of the downstream gene CCND1 was increased in HBC ER+ and CMTs compared to healthy tissues. Membranous and cytoplasmic protein expression of β-catenin were strongly negatively correlated in all 3 species. Tumors showed an increased protein expression of YAP/TAZ when compared to healthy tissues. Notably, YAP/TAZ expression was higher in triple negative breast cancers when compared to HBC ER+ and in FMTs when compared to CMTs. The mRNA expression of β-catenin, YAP, TAZ, CTGF, and ANKRD1 was not different between tumors and healthy mammary gland in the 3 species. This study demonstrates deregulation of Wnt/β-catenin and Hippo pathways in mammary tumors, which was more evident at the protein rather than the mRNA level. Wnt/β-catenin and Hippo pathways seem to be involved in mammary carcinogenesis and therefore represent interesting therapeutic targets that should be further investigated.

Statins downregulateYAPandTAZand exert anti‐cancer effects in canine mammary tumour cells

“…In the nucleus, YAP and TAZ bind mainly to TEA domain family member (TEAD) transcription factors to regulate the transcriptional activity of target genes involved in diverse processes [19][20][21][22] Hippo dysregulation has also been linked to various cancers in humans 19,[23][24][25][26][27] and dogs. [28][29][30][31] In breast cancer cells, altered transcriptional activity of Hippo transcriptional target genes has been shown to result in enhanced cell proliferation, cell migration, stem cell self-renewal, epithelial-tomesenchymal transition, metastasis and drug resistance. [32][33][34] Additionally, overexpression of the Hippo effectors YAP and (more importantly) TAZ has been detected in human breast cancer and canine mammary gland tumours.…”

“…This pathway consists of an intracellular serine/threonine kinase cascade that regulates the activity of two functionally redundant transcriptional co‐activators, Yes‐associated protein 1 (YAP) and Transcriptional coactivator with PDZ‐binding motif (TAZ). In the nucleus, YAP and TAZ bind mainly to TEA domain family member (TEAD) transcription factors to regulate the transcriptional activity of target genes involved in diverse processes 19–22 Hippo dysregulation has also been linked to various cancers in humans 19,23–27 and dogs 28–31 …”

Bridging the Species Gap: Morphological and Molecular Comparison of Feline and Human Intestinal Carcinomas

“…Because β-catenin score did not correlate with malignancy, Uneyama et al concluded from their IHC results that dysregulated β-catenin is likely not an important player in feline intestinal tumorigenesis; however, accumulation of β-catenin was evident in 60% of their cases [ 12 ]. Our immunohistochemical examination of feline intestinal carcinomas (22.5% of cases positive for nuclear β-catenin) as well as the high expression of active β-catenin in feline mammary tumors compared to healthy tissue [ 41 ], prompted us to further investigate the role of this key protein in the entity of feline intestinal cancer.…”

Diagnostic immunohistochemistry of primary and secondary central nervous system neoplasms of dogs and cats

“…Although a comprehensive review of mammary carcinoma IHC is not the purpose of our review, IHCs such as PR and estrogen receptor could be useful in a diagnostic setting to establish the origin of the primary tumor if the morphology supports the diagnosis of carcinoma. 66 Secondary CNS round-cell neoplasms typically occur as part of widespread neoplasia and include mainly lymphoma and histiocytic sarcoma. 18,20,36,70,73 Diagnostic confirmation for these neoplasms is similar to that described above for primary CNS round-cell neoplasms.…”