Loss of the receptors ER, PR and HER2 promotes USP15-dependent stabilization of PARP1 in triple-negative breast cancer
Abstract
Poly(ADP-ribose) polymerase 1 (PARP1) is essential for the progression of several types of cancers. However, whether and how PARP1 is stabilized to promote genomic stability in triple-negative breast cancer (TNBC) remains unknown. Here, we demonstrated that the deubiquitinase USP15 interacts with and deubiquitinates PARP1 to promote its stability, thereby stimulating DNA repair, genomic stability and TNBC cell proliferation. Two PARP1 mutations found in individuals with breast cancer (E90K and S104R) enhanced the PARP1-USP15 interaction and suppressed PARP1 ubiquitination, thereby elevating the protein level of PARP1. Importantly, we found that estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) inhibited USP15-mediated PARP1 stabilization through different mechanisms. ER bound to the USP15 promoter to suppress its expression, PR suppressed the deubiquitinase activity of USP15, and HER2 abrogated the PARP1-USP15 interaction. The specific absence of these three receptors in TNBC results in high PARP1 levels, leading to increases in base excision repair and female TNBC cell survival.
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USP15 shows dual effects in tumorigenesis; USP15 copy number is increased in glioblastoma, breast cancer, and ovarian cancer, but decreased in pancreatic cancer.
“Due to the conflicting functions of substrates, USP15 shows dual effects in tumorigenesis. For instance, USP15 copy number is increased in glioblastoma, breast cancer, and ovarian cancer, but decreased in pancreatic cancer40,52,55–58.”
From Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis (2024) · cites this paper as [58]
Cites
Konstantinopoulos, P. A., Barry, W. T., Birrer, M., Westin, S. N., Cadoo, K. A., Shapiro, G. I., Mayer, E. L., O'Cearbhaill, R. E., Coleman, R. L., Kochupurakkal, B., et al. (2019) · The Lancet Oncology · doi:10.1016/s1470-2045(18)30905-7 · Cited by 263 · see citing works
Peng, Y., Liao, Q., Tan, W., Peng, C., Hu, Z., Chen, Y., Li, Z., Li, J., Zhen, B., Zhu, W., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09232-8 · Cited by 104 · see citing works
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Zhang, Z., Wu, Y., Fu, J., Yu, X., Su, Y., Jia, S., Cheng, H., Shen, Y., He, X., Ren, K., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-48173-9 · Cited by 14 · see citing works
“For instance, USP15 copy number is increased in glioblastoma, breast cancer, and ovarian cancer, but decreased in pancreatic cancer 40,52,55 – 58 .”
Background
- Authors
- Sun, X., Tang, H., Chen, Y., Chen, Z., Hu, Z., Cui, Z., Tao, Y., Yuan, J., Fu, Y., Zhuang, Z., He, Q., Li, Q., Xu, X., Wan, X., Jiang, Y., & Mao, Z.
- Affiliations
- Tongji University (CN)
- Corresponding author
- Jiang, Ying
- Mao, Zhiyong
- ORCID
- Venue
- Nature Cancer
- Published
- 2023-04-03
- Volume
- 4
- Issue
- 5
- Pages
- 716-733
- ISSN
- 2662-1347 (ISSN-L)
- OpenAlex
- W4362523525
- Cited by
- 66
- References
- 2
- Citations by year
- 2026: 16 · 2025: 28 · 2024: 20 · 2023: 2
- FWCI
- 8.02
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature Cancer (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81972457, 32171288, 82071565, 32270750)
- National Key R&D Program of China
- Topics
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- triple-negative breast cancer, PARP1, USP15, deubiquitination, protein stabilization, estrogen receptor, progesterone receptor, HER2, base excision repair, genome stability, DNA repair, hormone receptor signaling
- MeSH terms
- Poly (ADP-Ribose) Polymerase-1, Deubiquitinating Enzymes, Female, Humans, Receptors, Estrogen, Receptors, Progesterone, Genomic Instability, Ubiquitin-Specific Proteases, Triple Negative Breast Neoplasms
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