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Resistance to BETi in breast cancer: more than meets the eye

Breast cancer is the second most common cancer globally (1), with about 70% of patients diagnosed with estrogen receptor-positive (ER+) breast cancer. These patients typically receive endocrine therapies targeting the estrogen receptor, but approximately half of high-grade diseases will likely progress (2), highlighting the urgent need for new and effective treatment options.

Sicong Zhang, PhD

Supported by a 2018 AACR-John and Elizabeth Leonard Family Foundation Basic Cancer Research Fellowship, Dr. Sicong Zhang investigated why BET inhibitors (BETi), a promising class of anti-cancer drugs, have failed to show efficacy in clinical trials for ER+ breast cancer patients (3).

The bromodomain (BD) and extra-terminal (ET) domain (BET) family of proteins (BRD2, BRD3, BRD4) are transcriptional cofactors that play critical roles in estrogen-dependent gene expression and tumor growth (4). These proteins contain two tandem bromodomains that bind to acetylated lysines of histones and an extraterminal domain involved in the recruitment of other transcriptional cofactors (4). BET inhibitors (BETi) bind to the bromodomains, displacing BET proteins from chromatin and inhibiting proliferation in a subset of cancers (3, 6).

Dr. Zhang confirmed that although many estrogen-dependent genes were repressed by BETi, important oncogenic targets such as MYC and CCND1 remained highly induced, primarily by the long isoform of BET family protein BRD4 (BRD4L) (7). He pointed out that “this suggests that resistance to BETi occurs early in treatment.”  Given, however, that BRD4 depletion significantly increased the antiproliferative activity of BETi, Dr. Zhang underscored that “our findings suggest that combining BETi with strategies targeting BRD4L or its BD-independent interactions could improve therapeutic outcomes.”

The transcriptional coactivator complex Mediator participates in estrogen-regulated gene expression (8). Dr. Zhang demonstrated that BRD4’s interactions with Mediator were crucial for BRD4’s recruitment to ER target genes, in a manner that was independent of BRD4’s bromodomains. Additional co-immunoprecipitation experiments showed a bromodomain-independent interaction of BRD4 with transcription elongation factors SPT5, SPT6, and PAF1C, with the interaction with PAF1C having the greatest impact on BET family-induced transcription.

Dr. Zhang shared that his work “aims to uncover the molecular mechanisms behind the BD-independent functions of BET proteins, with the goal of developing more effective strategies to target these proteins and overcome endocrine resistance.” He pointed out that the AACR-John and Elizabeth Leonard Family Foundation Basic Cancer Research Fellowship provided him with the opportunity to transition into a new area of research and broaden his understanding of transcriptional regulation. “This experience has significantly shaped my approach to studying cancer biology and therapeutic resistance,” he noted.  Moving forward, he seeks to “investigate other transcriptional regulators as potential therapeutic targets to improve treatment outcomes for breast cancer patients, including those undergoing chemotherapy.”

 References:

  1. Ferlay J, Ervik M, Lam F, Laversanne M, Colombet M, Mery L, et al. Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for Research on Cancer. 2024; Available from: https://gco.iarc.who.int/today, accessed [31 December 2024]
  2. Pan H, Gray R, Braybrooke J, Davies C, Taylor C, McGale P, et al. 20-Year Risks of Breast-Cancer Recurrence after Stopping Endocrine Therapy at 5 Years. N Engl J Med 2017; 377:1836-1846
  3. Cescon DW, Hilton J, Murilo SM, Layman RM, Pluard T, Yeo B, et al. A Phase I/II Study of GSK525762 Combined with Fulvestrant in Patients with Hormone Receptor-positive/HER2-negative Advanced or Metastatic Breast Cancer. Clin Cancer Res.  2024; 30:334-43
  4. Murakami S, Nagari A, Chae M, Camacho CV, Kraus WL. Distinct Roles for BET Family Members in Estrogen Receptor α Enhancer Function and Gene Regulation in Breast Cancer Cells. Mol Cancer Res. 2019; 17: 2356-68
  5. Wang Z-Q, Zhang Z-C, Yu Y-Y, Pi Y-N, Lou S-H, Liu T-B, et al. Bromodomain and extraterminal (BET) proteins: biological functions, diseases and targeted therapy. Signal Transduction and Targeted Therapy. 2023; 8:420
  6. Flippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, et al. Selective inhibition of BET bromodomains. Nature. 2010; 468: 1067-73
  7. Zhang S, Roeder RG. Resistance of estrogen receptor function to BET bromodomain inhibition is mediated by transcriptional coactivator cooperativity. Nature Structural & Molecular Biology. 2024; doi: 10.1038/s41594-024-01384-6
  8. Weber H, Garabedian MJ. The Mediator Complex in Genomic and Non-Genomic Signaling in Cancer. Steroids. 2017; 133:8-14