Hippo-TAZ signaling is the master regulator of the onset of triple-negative basal-like breast cancers.
Proc Natl Acad Sci U S A
; 119(29): e2123134119, 2022 07 19.
Article
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| MEDLINE
| ID: mdl-35858357
ABSTRACT
Breast cancer is the most frequent malignancy in women worldwide. Basal-like breast cancer (BLBC) is the most aggressive form of this disease, and patients have a poor prognosis. Here, we present data suggesting that the Hippo-transcriptional coactivator with PDZ-binding motif (TAZ) pathway is a key driver of BLBC onset and progression. Deletion of Mob1a/b in mouse mammary luminal epithelium induced rapid and highly reproducible mammary tumorigenesis that was dependent on TAZ but not yes-associated protein 1 (YAP1). In situ early-stage BLBC-like malignancies developed in mutant animals by 2 wk of age, and invasive BLBC appeared by 4 wk. In a human estrogen receptor+ luminal breast cancer cell line, TAZ hyperactivation skewed the features of these luminal cells to the basal phenotype, consistent with the aberrant TAZ activation frequently observed in human precancerous BLBC lesions. TP53 mutation is rare in human precancerous BLBC but frequent in invasive BLBC. Addition of Trp53 deficiency to our Mob1a/b-deficient mouse model enhanced tumor grade and accelerated cancer progression. Our work justifies targeting the Hippo-TAZ pathway as a therapy for human BLBC, and our mouse model represents a powerful tool for evaluating candidate agents.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Lesiones Precancerosas
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Neoplasias de la Mama Triple Negativas
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Vía de Señalización Hippo
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Neoplasias Mamarias Experimentales
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Año:
2022
Tipo del documento:
Article
País de afiliación:
Japón