Genetic Deletion or Pharmacologic Inhibition of PIM1 Impairs Breast Cancer Growth and Metastasis 276 views

Metastatic breast cancers often do not respond to currently available therapies, highlighting a need for new drug targets. Expression of PIM1 is upregulated in a significant percentage of breast cancers. PIM1 expression is also significantly increased in metastatic breast cancers compared to non-metastatic breast cancer patients. We hypothesized that PIM1 plays an important role in progression and metastasis of breast cancer. Knockdown/deletion of PIM1 significantly inhibited the proliferation, migration, and invasion of several breast cancer cell lines. To assess the in vivo role of PIM1 in breast cancer progression and metastasis, we crossed PIM1 knockout mice with MMTV-PyMT metastatic breast cancer mouse model. We found that deletion of PIM1 significantly inhibited tumor growth and reduced lung metastasis in these mice. Pharmacologic inhibition of PIM1 kinase using TP-3654 significantly inhibited cell proliferation, migration, and invasion in breast cancer cells, and reduced breast tumor growth and lung metastasis in MMTV-PyMT mice. We also found that PIM1 deletion or inhibition decreased EMT markers SLUG and Vimentin and pro-metastatic marker c-MET. RNA-seq analysis showed genes related to translation, proliferation, EMT and metastasis pathways were affected by PIM1 depletion or inhibition. Together, these results suggest that PIM1 plays an important role in the progression and metastasis of breast cancer.

PHD (Doctor of Philosophy)

Breast Cancer; TNBC; Triple Negative; PIM1; Metastasis

English

2023-04-29