Abstract LB225: Regulation of breast cancer stem cell identity by PLK1 and FOXC2

Abstract One of the main drivers for the drastic reduction in survival rates caused by metastatic breast cancer is attributed to Epithelial-to-Mesenchymal Transition (EMT). During embryonic development and wound healing, EMT plays a vital role and during cancer pathogenesis, cancer cells reactivate this program to gain plasticity, migration, and invasion promoting metastasis. In addition, EMT also plays a crucial role in generating a subpopulation of highly resilient tumor cells known as cancer stem cells (CSCs). Moreover, following conventional treatment, residual tumor cells that remain after treatment tend to exhibit CSC properties. EMT-induced cancer stem cells exhibit heightened plasticity and stemness, significantly fueling the metastatic spread of cancer and enhancing the endurance and adaptability throughout the process of metastasis. Thus, understanding the molecular intricacies governing stem cell properties holds immense potential for developing targeted therapies to target metastasis and the development of resistance to treatments. To further elucidate EMT-induced cancer stem cell generation, our lab has demonstrated that the Polo-like kinase 1 (PLK1), an important G2/M regulator, plays an important role in the generation of CSCs through Forkhead box protein C2 (FOXC2). Most importantly, we have shown that the FOXC2 transcription factor, known to be crucial in embryonic development, now has emerging roles in metastatic cancer progression. FOXC2 is positioned at the center of the complex network of signal transduction pathways and functions downstream of most EMT-inducing transcription factors. FOXC2 is necessary for the acquisition and maintenance of stem cell property. In addition, we found that phosphorylation of FOXC2 by PLK1 stabilizes, and inhibition of PLK1 causes a decrease in FOXC2 and stemness in cancer cells. This led us to hypothesize that EMT-induced CSC generation is driven by the PLK1-FOXC2 axis. By expressing phosphomimetic and non-phosphorylatable FOXC2 mutants in breast cancer cell lines, we show that PLK1 phosphorylation is necessary for gaining stemness and an increase in symmetric self-renewal type of stem cell division. Evidence will be presented as to how we are targeting the PLK1-FOXC2 axis to make tumors sensitive to standard-of-care treatments. Citation Format: Joanna Joyce Maddela, Maria Castaneda, Petra den Hollander, Nick Kuburich, Sendurai Mani. Regulation of breast cancer stem cell identity by PLK1 and FOXC2 abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB225.