The PIM kinase family comprises three constitutively active serine/threonine kinases that affect cell proliferation, survival, and motility, especially when upregulated in hematological malignancies or solid tumors, such as breast cancer. Furthermore, in estrogen receptor α (ERα)-expressing (ER+) breast cancer cells, PIM expression is upregulated in response to estrogen stimulation.

The aim of this PhD project was to explore the physiological roles of PIM kinases (PIMs) and their substrates in ER+ luminal A breast cancer. A variety of pharmacological PIM inhibitors and genetically modified cell lines were used in experiments, where the effects of phosphorylation on the activity of three novel PIM substrates (Notch3, LKB1, and ERα) were investigated. In study I, PIM-catalyzed phosphorylation of Notch3 was shown to inhibit Notch canonical signaling by disrupting interaction with CSL, a crucial component of the Notch transcriptional complex. Despite this, phosphorylated Notch3 supported tumor growth in the chick chorioallantoic membrane (CAM) xenograft model, hinting at an oncogenic CSLindependent Notch3 signaling mechanism. In study II, PIMs were shown to phosphorylate the tumor suppressor LKB1, and in doing so, reduce its catalytic capacity. Moreover, the growth of CAM tumors was slower when the xenografted cells lacked both LKB1 and PIMs, suggesting that PIMs could be a promising therapeutic target for cancer patients with LKB1-deficient tumors. Study III demonstrated that PIMs phosphorylate ERα and play a key role in regulating Erα signaling. While PIMs are known to contribute to resistance against various cancer therapies, we found no evidence that they are involved in endocrine therapy resistance in breast cancer.

Collectively, these study results provide further insight into how PIMs impact breast cancer cell signaling mechanisms.d