High cyclin E1 protein, but not gene amplification, is prognostic for basal-like breast cancer

Aziz, D; Lee, C; Chin, V; Fernandez, KJ; Phan, Z; kConFab Investigators; AOCS Study Group; Waring, P; Caldon, CE

Author(s): Aziz, D; Lee, C; Chin, V; Fernandez, KJ; Phan, Z; kConFab Investigators; AOCS Study Group; Waring, P; Caldon, CE;
Details: Publication Year 2022-07,Volume 8,Issue #4,Page 355-370
Journal Title: Journal of Pathology: Clinical Research
Publication Type: Research article
Abstract: Basal-like breast cancer (BLBC) has a greater overlap in molecular features with high-grade serous ovarian cancer (HGSOC) than with other breast cancer subtypes. Similarities include BRCA1 mutation, high frequency of TP53 mutation, and amplification of CCNE1 (encoding the cyclin E1 protein) in 6-34% of cases, and these features can be used to group patients for targeted therapies in clinical trials. In HGSOC, we previously reported two subsets with high levels of cyclin E1: those in which CCNE1 is amplified, have intact homologous recombination (HR), and very poor prognosis; and a CCNE1 non-amplified subset, with more prevalent HR defects. Here, we investigate whether similar subsets are identifiable in BLBC that may allow alignment of patient grouping in clinical trials of agents targeting cyclin E1 overexpression. We examined cyclin E1 protein and CCNE1 amplification in a cohort of 76 BLBCs and validated the findings in additional breast cancer datasets. Compared to HGSOC, CCNE1 amplified BLBC had a lower level of amplification (3.5 versus 5.2 copies) and lower relative cyclin E1 protein, a lack of correlation of amplification with expression, and no association with polyploidy. BLBC with elevated cyclin E1 protein also had prevalent HR defects, and high-level expression of the cyclin E1 deubiquitinase ubiquitin-specific protease 28 (USP28). Using a meta-analysis across multiple studies, we determined that cyclin E1 protein overexpression but not amplification is prognostic in BLBC, while both cyclin E1 overexpression and amplification are prognostic in HGSOC. Overall CCNE1 gene amplification is not equivalent between BLBC and HGSOC. However, high cyclin E1 protein expression can co-occur with HR defects in both BLBC and HGSOC, and is associated with poor prognosis in BLBC.
Keywords: *Breast Neoplasms/genetics/metabolism/pathology; Carcinoma, Basal Cell/genetics/metabolism/pathology; *Cyclin E/genetics/metabolism; Female; Gene Amplification; Humans; *Oncogene Proteins/genetics/metabolism; *Ovarian Neoplasms/genetics/metabolism/pathology; Prognosis; Ubiquitin Thiolesterase/genetics/metabolism; 19q12; CCNE1 amplification; Usp28; basal-like breast cancer; cyclin E1; high-grade serous ovarian cancer; homologous recombination deficiency
Department(s): Laboratory Research
PubMed ID: 35384378
Publisher's Version: https://doi.org/10.1002/cjp2.269
Open Access at Publisher's Site: https://doi.org/10.1002/cjp2.269
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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Last Modified: 2024-09-26 05:48:04