The Hippo Transducers TAZ and YAP in Breast Cancer: Oncogenic Activities and Clinical Implications
Introduction
Over the past decade, advances in our understanding of breast cancer (BC) biology have been accompanied by the development of new treatments and combination therapies, which have significantly expanded therapeutic options and improved patient outcomes. A large-scale molecular characterization effort has refined the taxonomy of BC, revealing multiple molecular and clinical subtypes, each defined by specific molecular alterations and differing sensitivities to hormone therapy, chemotherapy, and targeted agents. While this has added complexity to BC biology, it has also expanded the pool of potential targetable alterations and candidate biomarkers for patient stratification and therapy selection.
Among emerging oncogenic signals, strong evidence has highlighted the tumor-promoting roles of the transcriptional co-activator with PDZ-binding motif (TAZ) and the Yes-associated protein (YAP). TAZ and YAP are key components of the Hippo signaling pathway, an evolutionarily conserved regulator of tissue growth. In animal models, perturbations in this pathway have been linked to tissue overgrowth and tumorigenesis. In human cancers, with the exception of neurofibromin 2 (NF2), somatic or germline mutations in core Hippo pathway components are rare. Instead, TAZ and YAP activation in cancers appears to result from functional disruptions of Hippo-mediated control or crosstalk with other perturbed pathways.
Upstream Hippo components inhibit TAZ and YAP through phosphorylation, preventing their nuclear translocation and blocking the transcriptional program they drive. Beyond this, TAZ and YAP activation is regulated by a wide range of inputs, including cell junction integrity, extracellular signals, and metabolic pathways.
Mechanisms of TAZ and YAP Activation
Originally discovered in Drosophila melanogaster, the Hippo pathway was later recognized as a conserved regulator of tissue growth in mammals. The core Hippo module includes the serine/threonine kinases MST1 and MST2, LATS1 and LATS2, scaffold proteins such as SAV1, and regulatory subunits MOB1A and MOB1B. When active, MST1/2 and SAV1 form a complex that phosphorylates and activates LATS1/2, which in turn phosphorylates TAZ and YAP. This phosphorylation prevents their interaction with TEAD transcription factors and other partners, retaining TAZ and YAP in the cytoplasm and targeting them for degradation.
Various upstream signals, particularly those related to cell-cell adhesion and apical-basal polarity, block TAZ/YAP nuclear activities. Disruption of these signals, common in cancer cells with altered adhesive properties, relieves inhibition of TAZ/YAP. Additionally, the actin cytoskeleton and Rho GTPases play roles in mechanotransduction, allowing physical cues to modulate TAZ/YAP activity. The mevalonate pathway also regulates TAZ/YAP by controlling Rho GTPases.
Moreover, TAZ/YAP have been integrated into the Wnt signaling pathway. Without Wnt stimulation, TAZ/YAP are sequestered in the cytoplasm and contribute to β-catenin degradation. When Wnt ligands activate the pathway, TAZ/YAP are released, and both β-catenin and TAZ/YAP transcriptional programs are activated.
Overall, TAZ/YAP regulation is context-dependent, shaped by spatial, tissue, and environmental factors. Although much has been learned about their activation and biological outcomes, the molecular targets of TAZ/YAP remain largely unexplored, with only a few genes identified so far.
Oncogenic Activities Mediated by TAZ and YAP in Breast Cancer
TAZ and YAP overexpression is common across different BC subtypes, including luminal, HER2-positive, and triple-negative tumors. In preclinical models, TAZ and YAP promote cancer cell proliferation, survival, migration, metastasis, chemotherapy resistance, epithelial-to-mesenchymal transition (EMT), and cancer stem cell (CSC) traits.
TAZ was first shown to transform non-tumorigenic mammary cells (MCF10A), inducing spindle-shaped morphology and increased invasiveness. This transformation required TAZ interaction with TEAD transcription factors. TAZ mutations preventing Hippo-mediated phosphorylation led to sustained tumorigenic activity. Similar roles were observed for YAP in transformation, EMT induction, and growth in luminal-type BC models.
TAZ and YAP have been implicated in metastasis, with TAZ knockdown reducing migration and invasion, and involvement in bone metastases through interactions with hypoxia-inducible factor 1α. YAP contributes to metastasis via TEAD interactions and loss of metastasis suppressor proteins, such as LIFR.
In the tumor microenvironment, YAP activity is essential for maintaining cancer-associated fibroblasts (CAFs), supporting tumor growth and metastasis through matrix remodeling and mechanotransduction.
Controversy exists regarding YAP’s role, with evidence suggesting both oncogenic and tumor-suppressive functions, depending on context. YAP may promote apoptosis through interactions with p73 and has been observed to act as a tumor suppressor in certain settings.
TAZ/YAP and Breast Cancer Stem Cells
Cancer stem cells (CSCs) possess self-renewal capabilities and can recreate the parental tumor, contributing to therapy resistance and disease recurrence. The Hippo pathway regulates normal tissue stem cells, and TAZ/YAP have been linked to CSC traits in BC.
Breast CSCs are characterized by a CD44+/CD24−/low phenotype and rely on pathways like Hedgehog and Notch for self-renewal. TAZ supports CSC self-renewal and tumor-forming abilities, and its activation in non-CSCs can induce stem-like properties.
In patient-derived xenograft models, TAZ silencing reduced metastasis and enhanced chemotherapy-induced cell death, supporting its role in chemoresistance. Other studies have linked TAZ activity to hypoxia and extracellular matrix interactions, strengthening its connection to CSC maintenance and metastasis.
Understanding TAZ/YAP interaction with other CSC-related pathways could enable development of CSC-targeted therapies, an area of active clinical interest.
Clinical Implications: TAZ and YAP Expression in Breast Cancer
The heterogeneity of BC has driven efforts to identify reliable biomarkers for risk stratification and treatment selection. TAZ and YAP expression varies among BC subtypes and may be associated with clinical outcomes.
Analyses of large gene expression datasets have shown that TAZ/YAP activation signatures are enriched in high-grade tumors and correlate with metastasis and survival. High TAZ expression is linked to poor survival, especially in basal-like tumors. Immunohistochemical studies also associate high TAZ expression with aggressive features such as HER2 positivity and high Ki67.
TAZ expression increases from primary tumors to metastases, supporting its role in disease progression. In HER2-positive BC, TAZ-based scores predicted pathological complete response to neoadjuvant therapy in certain subgroups.
YAP expression patterns are more complex. In luminal A tumors, low YAP correlates with worse outcomes, whereas high nuclear YAP in other subtypes is linked to poor survival. Stromal YAP expression varies by subtype, suggesting diverse roles in tumor biology.
Future studies should focus on BC subtype-specific roles of TAZ/YAP, using standardized methods for assessment and considering both cytoplasmic and nuclear localization. Matched pre- and post-treatment samples could provide insights into dynamic changes during therapy.
Research in Progress and Conclusion
Preclinical evidence consistently implicates TAZ and YAP in breast carcinogenesis at multiple levels, making them attractive targets for clinical studies as biomarkers and therapeutic candidates.
The neoadjuvant setting offers an ideal platform for biomarker research, enabling the identification of predictive markers for treatment response and providing insights into long-term outcomes. There is also interest in the role of TAZ/YAP in bone metastases and skeletal-related events.
Therapeutic strategies to inhibit TAZ/YAP include porphyrin compounds like verteporfin, β-adrenergic receptor agonists like dobutamine, and tyrosine kinase inhibitors like dasatinib. Statins, through their effects on the mevalonate pathway, can also modulate TAZ/YAP activity and are being investigated in early BC patients to assess their impact on tumor biology.
Overall, while clinical data on TAZ and YAP remain preliminary, they highlight the need for further investigation into their roles as biomarkers TRULI and therapeutic targets in BC.