Authors:

Natalie Payne

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human epidermal growth factor 2 receptor (HER2), tends to have relatively higher PIM1 levels, relative to HER2+ and ER/PR+ breast cancer subtypes. PIM1 is recognized as a novel target for cancer therapies including in TNBC and while several inhibitors have been developed, none are currently FDA-approved for treatment. Our lab is invested in understanding the regulation of PIM1 expression in cancer to identify novel targeting of PIM1 and has previously reported that a targetable IL-6/JAK/STAT/PIM1 pathway is active in renal cell carcinoma (RCC). We find that the proinflammatory cytokine IL-6 is upregulated in PIM1 high RCC tumors acting through a downstream JAK/STAT signaling cascade to modulate PIM1 protein levels and expression. Thus, we hypothesize that an IL-6/JAK/STAT/PIM1 axis can be targeted in breast cancer taking advantage of FDA-approved agents. To investigate this axis, we are using human TNBC lines, MDA-MB-468 and MDA-MB-231, and an ER+/PR+ breast cancer line, MCF7. We selected ruxolitinib, an FDA-approved JAK inhibitor, to investigate whether PIM1 could be indirectly targeted via JAK blockade. Investigating clinical datasets from The Cancer Genome Atlas (TCGA), we found that TNBC demonstrates higher levels of PIM1 expression in comparison to normal breast cancer tumors. Analysis of clinical outcomes from TCGA also show that tumors with high expression of PIM1 (>median transcripts per million (TPM)) exhibit lower overall survival rates when compared with tumors with low expression of PIM1 (< median TPM)), accounting for a difference of almost 4 years lost, respectively. Immunoblotting analysis was used to assess PIM1 protein levels at baseline and in response to various doses of ruxolitinib. We find that the MDA-MB-468, MDA-MB-231, and MCF7 cell lines have high baseline PIM1 protein and that PIM1 protein levels generally decrease following treatment with ruxolitinib. Baseline secretion of IL-6 for each of the included cell lines was also measured via ELISA. We are currently conducting physiological relevant assays to determine the effect of JAK inhibition upstream of PIM1 on proliferation, migration, and viability. This work will provide insight on more effective therapeutic targets for breast cancers with high levels of PIM1 expression. Nathaniel Valentine:

Source:

Brown / Advanced Undergraduate Research Fellowships

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Co-authors:

Natalie Payne