Hippo-TAZ signaling is the master regulator of the onset of triple-negative basal-like breast cancers.

Autor: Soyama H; Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.; Division of Hepato-Biliary and Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan., Nishio M; Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan., Otani J; Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan., Sakuma T; Department of Pathology, Hyogo Cancer Center, Akashi, Hyogo 673-8558, Japan., Takao S; Department of Breast Surgery, Hyogo Cancer Center, Akashi, Hyogo 673-8558, Japan., Hara S; Department of Diagnostic Pathology, Kobe City Medical Center General Hospital, Kobe, Hyogo 650-0047, Japan., Masuda T; Department of Surgery, Kyushu University Beppu Hospital, Beppu, Oita 874-0838, Japan., Mimori K; Department of Surgery, Kyushu University Beppu Hospital, Beppu, Oita 874-0838, Japan., Toyokuni S; Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan., Lydon JP; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030., Nakao K; Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Kyoto 606-8397, Japan., Nishina H; Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Tokyo 113-8510, Japan., Fukumoto T; Division of Hepato-Biliary and Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan., Maehama T; Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan., Suzuki A; Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2022 Jul 19; Vol. 119 (29), pp. e2123134119. Date of Electronic Publication: 2022 Jul 11.
DOI: 10.1073/pnas.2123134119
Abstrakt: 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.
Databáze: MEDLINE
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