Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 35, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2100784118|1of9
Keywords
breast cancer; tripartite motif containing 47; nuclear factor kappa-B signaling; protein kinase C epsilon; protein kinase D3
Categories
Funding
- Ministry of Education, Culture, Sports, Science, and Technology (MEXT), Japan
- Japan Society for the Promotion of Science, Japan [15K15353, 17K10571, 20K08954]
- Uehara Memorial Foundation
- Yamaguchi Endocrine Research Foundation
- Kao Health Science Foundation
- Grants-in-Aid for Scientific Research [20K08954, 17K10571] Funding Source: KAKEN
Ask authors/readers for more resources
The study highlights the role of TRIM47 in promoting breast cancer proliferation and endocrine therapy resistance by forming a complex with PKC-ε and PKD3. These findings suggest TRIM47 and its associated kinases as potential diagnostic and therapeutic targets for breast cancer refractory to endocrine therapy.
Increasing attention has been paid to roles of tripartite motif- containing (TRIM) family proteins in cancer biology, often functioning as E3 ubiquitin ligases. In the present study, we focus on a contribution of TRIM47 to breast cancer biology, particularly to endocrine therapy resistance, which is a major clinical problem in breast cancer treatment. We performed immunohistochemical analysis of TRIM47 protein expression in 116 clinical samples of breast cancer patients with postoperative endocrine therapy using tamoxifen. Our clinicopathological study showed that higher immunoreactivity scores of TRIM47 were significantly associated with higher relapse rate of breast cancer patients (P = 0.012). As functional analyses, we manipulated TRIM47 expression in estrogen receptor-positive breast cancer cells MCF-7 and its 4-hydroxytamoxifen (OHT)-resistant derivative OHTR, which was established in a long-term culture with OHT. TRIM47 promoted both MCF-7 and OHTR cell proliferation. MCF-7 cells acquired tamoxifen resistance by overexpressing exogenous TRIM47. We found that TRIM47 enhances nuclear factor kappa-B (NF-KB) signaling, which further up-regulates TRIM47. We showed that protein kinase C epsilon (PKC-c) and protein kinase D3 (PKD3), known as NF-KB-activating protein kinases, are directly associated with TRIM47 and stabilized in the presence of TRIM47. As an underlying mechanism, we showed TRIM47-dependent lysine 27-linked polyubiquitination of PKC-c. These results indicate that TRIM47 facilitates breast cancer proliferation and endocrine therapy resistance by forming a ternary complex with PKC-c and PKD3. TRIM47 and its associated kinases can be a potential diagnostic and therapeutic target for breast cancer refractory to endocrine therapy.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available