About 10-20% of breast cancers are triple-negative breast cancers (TNBC) that have poorer outcomes and higher risk of recurrence compared to other breast cancer types. It is known that the mRNA and protein levels of TAZ (transcriptional co-activator with PDZ-binding motif) are preferentially higher in TNBC than in other breast cancer (BC) subclasses. Activation of TAZ has been correlated with high histological grade, conferral of breast cancer stem cell (CSC) traits, enhanced tumor metastasis, and poor outcome in BC patients. There is a fundamental gap in understanding how activation of TAZ contributes to tumor relapse and metastasis in TNBC patients. The continued existence of this gap represents an important problem because, until it is filled, it will be impossible to devise rational therapeutic approaches to help improve breast cancer patient survival. The long-term goal is to reduce morbidity in TNBC patients and help improve breast cancer patient survival. The overall objective of this application is to understand the molecular mechanisms by which TAZ initiates breast tumor progression and metastasis. The central hypothesis is that both TAZ-initiated promotion of cell cycle activity and expansion of transformed mammary stem cell (Ma-SC) populations are required for TAZ-initiated breast tumorigenesis. Our hypothesis has been formulated on the basis of our own preliminary data. The rationale for the proposed research is that once it is known how activation of TAZ initiates TNBC progression and metastasis, it will be possible to develop new and innovative approaches for treating TNBCs. To this end, we propose the following aims: (1) identify the critical downstream targets that are required for TAZ to initiate breast cancer progression; (2) determine how TAZ induces the formation of heterogeneous mammary tumors using a unique TAZ transgenic mouse model; and (3) determine the role of TAZ in breast tumor heterogeneity and its impact on tumor metastasis. As the outcome of this study, we expect to identify the critical targets of TAZ that are responsible for TAZ-initiated breast tumor progression and metastasis as well as to establish a well-characterized TAZ transgenic mouse model. Such results are expected to vertically advance our understanding of how TAZ activation contributes to TNBC relapse.
The relatively high relapse rate of patients with aggressive forms of breast cancer can be attributed to a small population of cancer stem cells (CSCs) residing within the tumor and specific targeting of this notorious population may provide novel and highly effective therapeutic strategies. Our objective in this proposal is to determine the roles and underlying mechanisms of TAZ activation in the regulation of breast CSC, breast tumorigenesis and metastasis, with a further goal to apply TAZ-regulated genes into practical use in breast cancer diagnosis and treatment.
| Denson, Kayla E; Mussell, Ashley L; Shen, He et al. (2018) The Hippo Signaling Transducer TAZ Regulates Mammary Gland Morphogenesis and Carcinogen-induced Mammary Tumorigenesis. Sci Rep 8:6449 |
| Azad, T; Janse van Rensburg, H J; Lightbody, E D et al. (2018) A LATS biosensor screen identifies VEGFR as a regulator of the Hippo pathway in angiogenesis. Nat Commun 9:1061 |
| Mussell, Ashley L; Denson, Kayla E; Shen, He et al. (2018) Loss of KIBRA function activates EGFR signaling by inducing AREG. Oncotarget 9:29975-29984 |
