HDAC inhibitors modulate Hippo pathway signaling in hormone positive breast cancer

被引：0
作者：
Lin, Ting-, I [1 ,2 ]
Tseng, Yi-Ru [1 ,2 ]
Dong, Min-Jyun [1 ,2 ]
Lin, Chih-Yi [1 ,2 ]
Chung, Wei-Ting [1 ,2 ]
Liu, Chun-Yu [1 ,3 ,4 ,6 ]
Tsai, Yi-Fang [3 ,4 ,5 ]
Huang, Chi-Cheng [3 ,4 ,5 ]
Tseng, Ling-Ming [3 ,4 ,5 ]
Chao, Ta-Chung [1 ,3 ,4 ,6 ]
Lai, Jiun-, I [1 ,2 ,3 ,4 ,6 ]
机构：
[1] Taipei Vet Gen Hosp, Dept Oncol, Div Med Oncol, Taipei, Taiwan
[2] Natl Yang Ming Chiao Tung Univ, Inst Clin Med, Taipei, Taiwan
[3] Natl Yang Ming Chiao Tung Univ, Sch Med, Taipei, Taiwan
[4] Taipei Vet Gen Hosp, Comprehens Breast Hlth Ctr, Taipei, Taiwan
[5] Taipei Vet Gen Hosp, Dept Surg, Div Gen Surg, Taipei, Taiwan
[6] Taipei Vet Gen Hosp, Ctr Immuno Oncol, Dept Oncol, Taipei City, Taiwan
来源：
CLINICAL EPIGENETICS | 2025年 / 17卷 / 01期
关键词：
ESTROGEN-RECEPTOR; TRANSCRIPTIONAL REPRESSION; DEACETYLASE INHIBITOR; CELL-CYCLE; EXPRESSION; LATS1/2; GROWTH; YAP1; OVEREXPRESSION; IDENTIFY;
D O I：
10.1186/s13148-025-01834-y
中图分类号：
R73 [肿瘤学];
学科分类号：
100214 ;
摘要：
Breast cancer has constantly been the leading causes of death in women, and hormone receptor (HR) positive, HER2 negative is the majority subtype. Histone deacetylase (HDAC) inhibitors (HDACi) have shown clinical benefit in HR ( +) breast cancer patients. The Hippo pathway is an important cellular pathway involving proliferation, cell contact, and cancer. Hippo pathway proteins YAP/TAZ are often viewed as pro-tumorigenic; however, recent studies support a role of YAP as a tumor suppressor in HR ( +) breast cancer. Few studies have investigated the link between HDACi and the Hippo pathway. In our study, we demonstrate that HDACi induces transcriptional downregulation of YAP expression, while conversely activating a TEAD-mediated transcriptional program with upregulation of canonical Hippo pathway genes. We subsequently identified four Hippo canonical genes (CCDC80, GADD45A, F3, and TGFB2) that were upregulated by HDACi and associated with significantly improved survival in a HR ( +) breast cancer cohort. We further validated experimentally that HR ( +) breast cancer cells treated with HDACi resulted in upregulation of CCDC80 and GADD45A. A pan-cancer analysis of TCGA database demonstrated lower CCDC80 and GADD45A expression in tumor tissue compared to non-tumor samples in BRCA (breast cancer), LAML (acute myeloid leukemia), and UCS (uterine carcinosarcoma). Further analysis of HR ( +) breast cancer patients in the METABRIC dataset revealed high CCDC80 and/or GADD45A expression associated with significantly better survival outcomes compared to patients with low expression. Our study provides evidence for a novel mechanism of HDACi clinical activity, as well as a potential role for CCDC80 and GADD45A in HR ( +) breast cancer.
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页数：14
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  • [1] Siegel R.L., Miller K.D., Jemal A., Cancer statistics, 2020, CA Cancer J Clin, 70, 1, pp. 7-30, (2020)
  • [2] Duggan C., Trapani D., Ilbawi A.M., Fidarova E., Laversanne M., Curigliano G., Et al., National health system characteristics, breast cancer stage at diagnosis, and breast cancer mortality: a population-based analysis, Lancet Oncol, 22, 11, pp. 1632-1642, (2021)
  • [3] Perou C.M., Sorlie T., Eisen M.B., van de Rijn M., Jeffrey S.S., Rees C.A., Et al., Molecular portraits of human breast tumours, Nature, 406, 6797, pp. 747-752, (2000)
  • [4] Goetz M.P., Toi M., Campone M., Sohn J., Paluch-Shimon S., Huober J., Et al., MONARCH 3: abemaciclib as initial therapy for advanced breast cancer, J Clin Oncol Off J Am Soc Clin Oncol, 35, 32, pp. 3638-3646, (2017)
  • [5] Hortobagyi G.N., Stemmer S.M., Burris H.A., Yap Y.S., Sonke G.S., Paluch-Shimon S., Et al., Ribociclib as first-line therapy for HR-positive, advanced breast cancer, N Engl J Med, 375, 18, pp. 1738-1748, (2016)
  • [6] Finn R.S., Martin M., Rugo H.S., Jones S., Im S.A., Gelmon K., Et al., Palbociclib and letrozole in advanced breast cancer, N Engl J Med, 375, 20, pp. 1925-1936, (2016)
  • [7] Jones R.H., Casbard A., Carucci M., Cox C., Butler R., Alchami F., Et al., Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): a multicentre, randomised, controlled, phase 2 trial, Lancet Oncol, 21, 3, pp. 345-357, (2020)
  • [8] Andre F., Ciruelos E., Rubovszky G., Campone M., Loibl S., Rugo H.S., Et al., Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer, N Engl J Med, 380, 20, pp. 1929-1940, (2019)
  • [9] Baselga J., Campone M., Piccart M., Burris H.A., Rugo H.S., Sahmoud T., Et al., Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer, N Engl J Med, 366, 6, pp. 520-529, (2012)
  • [10] Wang J., Xu B., Targeted therapeutic options and future perspectives for HER2-positive breast cancer, Signal Transduct Target Ther, 4, 1, (2019)
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