Abstract 4130: Atypical protein kinase C iota (PKC-ι) regulates an oncogenic positive feedback loop between the MAPK/JNK signaling pathway, AP-1 complex and TNF-α in triple negative breast cancer
Authors: Nuzhat Nowshin Oishee, Mahfuza Marzan, Khandker Mohammad Khalid, Abiral Hasib Shourav, Abigail Olatunji, Radwan Ebna Noor, Mildred Acevedo-Duncan
Journal: Cancer Research (2025)

Abstract Breast Cancer is the second most common cancer in the United States and consists of about 30% of all new female cancers each year. The average risk of a women developing breast cancer in her lifetime is about 13%. Atypical Protein Kinase C iota (PKC-ι) is over expressed in 88 of the 110 breast cancer cases (80.0%) and is highly active in the invasive progression of the disease. Therefore, considering PKC-ι as a novel therapeutic target is crucial. c-Jun is a Basic leucine zipper (bZIP) transcription factor and crucial component of activator protein-1 (AP-1) complex, which is also overexpressed in breast cancer and its oncogenic function regulates proliferation, apoptosis, metastasis and angiogenesis in breast cancer. c-Jun sits at the crossroad of the signaling network; hence, understanding the relationship between PKC-ι and c-Jun is fundamental. c-Jun is activated by the JNK pathway, which itself has its own oncogenic function and plays vital role in malignant transformation and metastasis in different cancer including breast cancer. In addition, the upstream markers of JNK are MKK7 and Tak1, which are part of the MAP2K and MAP3K families, respectively and these markers also play a pro-oncogenic role in breast cancer. The activation of these upstream markers further stimulates the phosphorylation and activation of JNK, which in turn activates c-Jun. Activated c-Jun forms homodimers and heterodimers in Activator Protein-1 complex (AP-1) complex, which also have oncogenic activity in cancer cell proliferation and apoptosis. The AP-1 complex further stimulates the pro-inflammatory cytokine TNF-α, which again stimulates the activation of the MAPK/JNKpathway. This indicates that there is an oncogenic positive feedback loop between these biomarkers, and it is hypothesized that PKC-ι regulates this positive feedback loop.This study examines the role played by PKC-ι in regulating the positive feedback loop between the MAPK/JNK pathway, AP1 complex, and TNF-α. Using ICA-1S, an inhibitor specific to PKC-ι, BT549 breast cancer cells were treated for 5 days (10μM dosage), and SDS-PAGE was conducted. Our results indicate that in BT549 cells, inhibition of PKC-ι with ICA-1S has significantly reduced the levels of Tak1, p-JNK, JNK, m-MKK7, MKK7, p-c-Jun, c-Jun, and TNF-α. These findings indicate that inhibiting PKC-ι can reduce the phosphorylation and activation of JNK and its upstream and downstream targets, and that inhibition of PKC-ι inhibits the oncogenic role of this positive feedback loop in breast cancer. Hence, it can be concluded that in BT549 triple negative breast cancer cells, PKC-ι regulates the oncogenic loop between MAPK/JNK pathway, AP-1 and TNF-α via the phosphorylation and activation of c-Jun, which further stimulates the activation of the entire loop. Citation Format: Nuzhat Nowshin Oishee, Mahfuza Marzan, Khandker Mohammad Khalid, Abiral Hasib Shourav, Abigail Olatunji, Radwan Ebna Noor, Mildred Acevedo-Duncan. Atypical protein kinase C iota (PKC-ι) regulates an oncogenic positive feedback loop between the MAPK/JNK signaling pathway, AP-1 complex and TNF-α in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4130.