Expression of the Hippo signalling effectors YAP and TAZ in canine mammary gland hyperplasia and malignant transformation of mammary tumours

Rico, Charlène; Boerboom, Derek; Paquet, Marilène

doi:10.1111/vco.12432

Cited by 7 publications

(11 citation statements)

References 24 publications

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“…Conversely, YAP protein expression did not vary between normal and neoplastic tissues. 61 In this study, we analyzed the mRNA expression of YAP, TAZ, CTGF, and ANKRD1, as well as the protein expression of YAP/TAZ in a subset of normal and tumor tissues of human, canine, and feline mammary gland. In all the 3 species, TAZ mRNA expression was not different between normal and tumor tissues and between different tumor subgroups.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…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.…”

Section: Introductionmentioning

confidence: 99%

“…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 …”

Section: Introductionmentioning

confidence: 99%

“…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‐to‐mesenchymal transition, metastasis and drug resistance 32–34 . Additionally, overexpression of the Hippo effectors YAP and (more importantly) TAZ has been detected in human breast cancer and canine mammary gland tumours 28 . Recent evidence demonstrates a critical role of Hippo pathway in cancer stem cell (CSC) biology.…”

Section: Introductionmentioning

confidence: 99%

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

Vigneau

Rico

Boerboom

et al. 2021

Vet Comparative Oncology

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Canine mammary tumours (CMTs) are the most common neoplasms in intact bitches, and few chemotherapeutic options are available for highly invasive and metastatic tumours. Recent studies have shown the potential involvement of dysregulated Hippo signalling in CMT development and progression. Statins can activate the Hippo pathway by blocking protein geranylgeranylation (GGylation), resulting in decreased expression and activity of the transcriptional co‐activators YAP and TAZ. In this study, we therefore sought to determine if statins could exert anti‐cancer effects in CMT cells. Our results demonstrate that Atorvastatin and Fluvastatin are cytotoxic to two CMT cell lines (CMT9 and CMT47), with ED50 values ranging from 0.95 to 23.5 μM. Both statins acted to increase apoptosis and promote cell cycle arrest. Both statins also decreased YAP and TAZ expression and reduced the mRNA levels of key Hippo transcriptional target genes known to be involved in breast cancer progression and chemoresistance (CYR61, CTGF and RHAMM). Moreover, both statins effectively inhibited cell migration and anchorage independent growth, but did not influence matrix invasion. Taken together, our results demonstrate for the first time that statins act upon the Hippo pathway in CMT cells to counteract several molecular and cellular hallmarks of cancer. These findings suggest that targeting the Hippo pathway with statins represents a novel and promising approach for the treatment canine mammary gland cancers.

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“…To obtain indirect information about YAP nuclear localization and function and the potential influence of the increase in pROCK-II Ser1366 in treated samples, pHH3 Ser10 , which is indicative for cell proliferation, was analyzed next. YAP is a potent driver of cell proliferation and was shown to promote epithelial hyperplasia, which we described for the FAK-siRNA-treated samples [ 75 ]. Consequently, an increase in proliferating keratinocytes in the epithelial equivalents would indirectly support the idea of an increase in YAP nuclear activity.…”

Section: Resultsmentioning

confidence: 99%

FAK Shutdown: Consequences on Epithelial Morphogenesis and Biomarker Expression Involving an Innovative Biomaterial for Tissue Regeneration

Wang

Steinberg

Dieterle

et al. 2021

IJMS

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By employing an innovative biohybrid membrane, the present study aimed at elucidating the mechanistic role of the focal adhesion kinase (FAK) in epithelial morphogenesis in vitro over 4, 7, and 10 days. The consequences of siRNA-mediated FAK knockdown on epithelial morphogenesis were monitored by quantifying cell layers and detecting the expression of biomarkers of epithelial differentiation and homeostasis. Histologic examination of FAK-depleted samples showed a significant increase in cell layers resembling epithelial hyperplasia. Semiquantitative fluorescence imaging (SQFI) revealed tissue homeostatic disturbances by significantly increased involucrin expression over time, persistence of yes-associated protein (YAP) and an increase of keratin (K) 1 at day 4. The dysbalanced involucrin pattern was underscored by ROCK-IISer1366 activity at day 7 and 10. SQFI data were confirmed by quantitative PCR and Western blot analysis, thereby corroborating the FAK shutdown-related expression changes. The artificial FAK shutdown was also associated with a significantly higher expression of filaggrin at day 10, sustained keratinocyte proliferation, and the dysregulated expression of K19 and vimentin. These siRNA-induced consequences indicate the mechanistic role of FAK in epithelial morphogenesis by simultaneously considering prospective biomaterial-based epithelial regenerative approaches.

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Expression of the Hippo signalling effectors YAP and TAZ in canine mammary gland hyperplasia and malignant transformation of mammary tumours

Cited by 7 publications

References 24 publications

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

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

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

FAK Shutdown: Consequences on Epithelial Morphogenesis and Biomarker Expression Involving an Innovative Biomaterial for Tissue Regeneration

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