Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer distinguished by the absence of estrogen and progesterone receptors, as well as the lack of amplification of human epidermal growth factor 2 (HER2) protein. Representing approximately 15% of all breast cancer patients, TNBC is associated with poor prognosis and limited treatment options. Chemotherapy remains the mainstay treatment option due to the absence of reliable targeted therapies, but the emergence of chemoresistance poses a significant challenge, resulting in high rates of treatment failure, particularly in metastatic cases. Therefore, understanding the molecular drivers of chemoresistance is crucial to improving patient outcomes.
Recent studies in the Khew-Goodall lab have identified Protein Kinase C delta (PKCδ) phosphorylated on a specific residue (henceforth denoted as p-PKCδ), which occurs in a portion of TNBC patients and correlates to poor prognosis. Various dysregulated signalling mechanisms have been linked to chemoresistance in TNBC, with increasing evidence suggesting a key role for autophagy, a cellular recycling process implicated in both normal physiology and cancer progression. Literature suggests PKCδ participates in autophagy regulation, and our data indicate that elevated p-PKCδ alters autophagic response following chemotherapeutic treatment, although the precise mechanisms remain unclear.
A potential mediator is VAMP3, a vesicle-associated membrane protein with established roles in autophagy. Phosphoproteomics has identified VAMP3 as a candidate substrate of p-PKCδ, suggesting p-PKCδ-driven phosphorylation of VAMP3 contributes to altered autophagy dynamics and chemoresistance in TNBC. By understanding the role of p-PKCδ and its substrates in mediating chemoresistance, this research endeavours to pave the way for the development of targeted therapies tailored to combat chemoresistance in TNBC, ultimately improving patient outcomes and quality of life.