1. Expression of the PIM1 protein was elevated in tumor samples from patients with MYC-positive triple negative breast cancer (TNBC), and was also associated with poor prognosis in patients.
2. After the inhibition of PIM1, mice showed decreased tumor growth as well as an increase in cell apoptosis.
Evidence Rating Level: 2 (Good)
Study Rundown: TNBC lacks various receptors that are typically targeted in cancer treatment, making it the subtype of breast cancer with the worst prognosis. The lack of receptors has also made it substantially more difficult to treat this subset of breast cancer due to an inability to target specific receptors. The goal of this study was to identify a novel protein characteristic of TNBC that could be targeted by drug.
Through a knockdown of various kinase proteins, it was discovered that the loss of PIM1 expression led to cell death in MYC-activated cells, MYC being a gene typically highly expressed in TNBC. In primary tumor samples from four clinical TNBC cohorts, PIM1 expression was significantly increased. Following these discoveries, cell lines and mouse models were used to test the effect of PIM1 inhibition on cancer cell growth. PIM1 inhibitors were found to be more effective on tumors containing cells with high PIM1 and MYC expression. The inhibition of PIM1 led to a significant decrease in the number of proliferating cells and an increase in cells undergoing apoptosis. Inhibition of PIM1 also led to a decrease in total MYC expression.
The discovery of PIM1 function in MYC-activated TNBC models could lead to a new therapeutic specific to this difficult-to-treat cancer subtype. Other tests will need to be performed to determine potential side effects as well as the toxicity of PIM1 inhibitors, but this study could lead to efficacious therapeutic options for patients that have TNBC.
In-Depth [animal study]: To identify potential therapeutic targets for TNBC, a kinome-wide MYC synthetic lethal shRNA screen was performed on human mammary epithelial cells to identify kinases necessary for the survival of MYC-expressing cells. Of the nine targets that were identified, the PIM1 kinase was involved in cell survival and growth and had the highest cell death differential.
Primary tumor samples from four clinical cohorts were then analyzed for PIM1 expression, and the mRNA expression of this gene was significantly elevated in patients with TNBC. This increased expression was also found to be associated with poor survival prognosis.
Mouse models were then used to test the efficacy of PIM1 inhibitors on tumor cell growth. In several models, mice were xenografted with various breast cancer cell lines. Transgenic mouse lines that developed MYC-expressing tumors were also generated. Ki67 staining showed a decrease in tumor cell proliferation in the treated cells with high MYC expression (p<0.0285). There was also an increased number of apoptotic cells, as determined through TUNEL staining. In addition, PIM1 inhibition was found to decrease MYC activity, elucidating the reason behind the increased efficacy of these inhibitors in high-expressing MYC cells. The treated mice were also found to have increased levels of p27 expression (p<0.034), a gene known to be positively correlated with the prognosis of TNBC.
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