Posted January 12, 2024

Ann Marie Pendergast, Ph.D., Duke University School of Medicine

Metastasis is the spread of cancer cells from the initial tumor site to another location of the body. For those living with breast cancer, the 5-year relative survival rate drops from 99% for localized breast cancer to only 30% for metastatic disease.¹ HER2-positive (HER2+) breast cancers have increased levels of HER2, a protein that promotes cell growth and is encoded by the ERBB2 gene. Patients with HER2+ breast cancer experience metastasis at higher levels, and brain metastasis, in particular, is common in these individuals. Breast cancer brain metastasis (BCBM) results in an overall decrease in the patient’s quality of life due to a myriad of complications including cognitive impairment, seizures, and brain nerve damage. Historically, HER2-targeted treatment therapies have not been successful in treating brain metastases due to both poor ability to cross the blood-brain barrier (BBB) and drug resistance. Previous research has shown that the Abelson (ABL) family kinases ABL1 and ABL2 are enzymes that play a role in the function and signaling of cell-surface receptors like HER2; hypothetically, inhibition of the ABL kinases could impair breast cancer metastasis to the brain and provide a new therapeutic target for BCBM.

With funding from a fiscal year 2017 (FY17) Breakthrough Award Funding Level 2, Dr. Ann Marie Pendergast and her team conducted research on ABL kinase inhibition in a mouse model of HER2+ BCBM and evaluated the effect on breast cancer progression and metastasis to help clarify its relationship with HER2. In mice treated with an inhibitor of ABL kinase, there was an 80% decrease in ABL kinase activity, decreased metastasis to the brain, and increased overall survival as compared to controls. These results were replicated and confirmed in several HER2+ brain metastatic cell lines, including a mouse model with a functional immune system, demonstrating that treatment with an ABL kinase inhibitor approved by the U.S. Food and Drug Administration (FDA) for other cancer types also inhibited brain metastases.

To understand the relationship of ABL and HER2, the investigators evaluated HER2 protein levels in three BCBM cell lines and observed that the inhibition of ABL kinase led to a reduction in HER2 protein, indicating a relationship between the ABL kinase and HER2 protein expression. Pendergast and her team tested whether ABL kinase inhibition altered ERBB2 transcription, HER2 protein stability, and/or translation of the corresponding messenger RNA (mRNA) into protein. Pharmacologic and genetic inhibition of ABL kinases resulted in little to no change in ERBB2 mRNA levels and did not affect HER2 protein stability. Rather, ABL kinase inhibition or depletion profoundly decreased HER2 protein levels by impairing ERBB2 mRNA translation, leading to a decrease in HER2 protein expression. RNA binding proteins, such as Y-box-binding protein 1 (YB-1), play an important role in regulation of protein synthesis by binding the mRNA. Interestingly, upon ABL kinase inhibition, Dr. Pendergast found the decline in HER2 protein levels was due to a decreased interaction between YB-1 and the HER2/ERBB2 mRNA. Further evaluation confirmed that reduced YB-1 expression resulted in a decreased number of HER2 proteins and a dramatic reduction of cell viability thus providing evidence that YB-1 is involved in HER2 regulation. Notably, the team found that loss of YB-1 expression in HER2+ breast cancer brain metastatic cells decreased HER2 protein levels and impaired brain metastatic outgrowth leading to improved survival in preclinical models.

To further understand the mechanistic relationship between ABL, YB-1, and HER2, the team conducted experiments assessing phosphorylation, a molecular process that governs protein activity and stability. The team found that ABL activity leads to YB-1 phosphorylation. This, in turn, revealed that ABL-mediated phosphorylation of YB-1 is required to promote HER2 protein synthesis. This discovery — ABL-YB-1 signaling, its control of HER2 protein synthesis, and the potential to treat HER2-driven brain metastases through inhibition of ABL — opens up a promising new therapeutic target mechanism.

While previous studies have examined HER2 overexpression regulation in tumors, the Pendergast team’s explorations of the cellular mechanisms behind HER2 protein synthesis, specifically in the context of brain metastasis, provide evidence for the mechanism of ABL-YB-1 signaling and its effects on the HER2 protein. The discovery that cancer cells expressing HER2 can be targeted by BBB-permeable ABL kinases, one of which is FDA-approved for other cancer types, suggests these drugs might be effective in treating HER2+ BCBM. Continued research on the ABL-YB-1 pathway and its regulation of HER2 may ultimately improve breast cancer treatment and decrease the development of metastasis, thereby improving patient outcomes.

References:

¹American Cancer Society. Survival Rates for Breast Cancer. Last revised 3/1/2023. https://www.cancer.org/cancer/types/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-survival-rates.html.

Publications:

McKernan CM, Khatri A, Hannigan M, et al. 2022. ABL kinases regulate translation in HER2+ cells through Y-box-binding protein 1 to facilitate colonization of the brain. Cell Reports 40(9):111268. https://doi.org/10.1016/j.celrep.2022.111268.

Links:

Public and Technical Abstracts: Identification of Actionable Networks Promoting Breast Cancer Progression and Brain Metastasis

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