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Updated: Feb 8, 2026
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
PIM1 kinase inhibition as a targeted therapy against triple-negative breast tumors with elevated MYC expression
Dai Horiuchi1,2,3,4, Roman Camarda1, Alicia Y Zhou1
1Department of Cell and Tissue Biology, University of California, San Francisco (UCSF), San Francisco, California, USA.
Abstract:
Triple-negative breast cancer (TNBC), in which cells lack expression of the estrogen receptor (ER), the progesterone receptor (PR) and the ERBB2 (also known as HER2) receptor, is the breast cancer subtype with the poorest outcome. No targeted therapy is available against this subtype of cancer owing to a lack of validated molecular targets. We previously reported that signaling involving MYC-an essential, pleiotropic transcription factor that regulates the expression of hundreds of genes-is disproportionally higher in triple-negative (TN) tumors than in receptor-positive (RP) tumors. Direct inhibition of the oncogenic transcriptional activity of MYC has been challenging to achieve. Here, by conducting a shRNA screen targeting the kinome, we identified PIM1, a non-essential serine-threonine kinase, in a synthetic lethal interaction with MYC. PIM1 expression was higher in TN tumors than in RP tumors and was associated with poor prognosis in patients with hormone- and HER2-negative tumors. Small-molecule PIM kinase inhibitors halted the growth of human TN tumors with elevated MYC expression in patient-derived tumor xenograft (PDX) and MYC-driven transgenic mouse models of breast cancer by inhibiting the oncogenic transcriptional activity of MYC and restoring the function of the endogenous cell cycle inhibitor, p27. Our findings warrant clinical evaluation of PIM kinase inhibitors in patients with TN tumors that have elevated MYC expression.
Insights
Triple-negative breast cancer (TNBC) has poor outcomes due to a lack of targeted therapies. Researchers found that inhibiting PIM1 kinase, which is elevated in TNBC, halts tumor growth by targeting MYC signaling.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Triple-negative breast cancer (TNBC) lacks targeted therapies and has the poorest prognosis among breast cancer subtypes.
- MYC signaling is disproportionately higher in TNBC compared to receptor-positive tumors, presenting a potential therapeutic vulnerability.
- Directly inhibiting MYC's oncogenic activity has been a significant challenge in cancer treatment.
Purpose of the Study:
- To identify novel therapeutic targets for triple-negative breast cancer.
- To investigate the role of MYC signaling in TNBC pathogenesis.
- To evaluate PIM1 kinase as a potential therapeutic target in TNBC.
Main Methods:
- Conducted a shRNA screen targeting the kinome to identify genes synthetically lethal with MYC.
- Assessed PIM1 expression levels in human TNBC tumors and correlated them with patient prognosis.
- Tested small-molecule PIM kinase inhibitors in patient-derived tumor xenograft (PDX) and MYC-driven transgenic mouse models of breast cancer.
Main Results:
- Identified a synthetic lethal interaction between PIM1 kinase and MYC.
- Found that PIM1 expression is elevated in TNBC and associated with poor prognosis.
- Demonstrated that PIM kinase inhibitors effectively halt TNBC tumor growth in preclinical models by inhibiting MYC transcriptional activity and restoring p27 function.
Conclusions:
- PIM1 kinase represents a promising therapeutic target for triple-negative breast cancer.
- PIM kinase inhibitors show potential for treating TNBC with elevated MYC expression.
- Clinical evaluation of PIM kinase inhibitors in patients with TNBC is warranted.
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