PKCλ/ι signaling promotes triple-negative breast cancer growth and metastasis

Triple-negative breast cancer (TNBC) is a distinct breast cancer subtype defined by the absence of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2/neu), and the patients with TNBC are often diagnosed with higher rates of recurrence and metastasis. Because of the absence of ER, PR and HER2/neu expressions, TNBC patients are insensitive to HER2-directed and endocrine therapies available for breast cancer treatment. Here, we report that expression of atypical protein kinase C isoform, PKC lambda/iota, significantly increased and activated in all invasive breast cancer (invasive ductal carcinoma or IDC) subtypes including the TNBC subtype. Because of the lack of targeted therapies for TNBC, we choose to study PKC lambda/iota signaling as a potential therapeutic target for TNBC. Our observations indicated that PKC lambda/iota signaling is highly active during breast cancer invasive progression, and metastatic breast cancers, the advanced stages of breast cancer disease that developed more frequently in TNBC patients, are also characterized with high levels of PKC lambda/iota expression and activation. Functional analysis in experimental mouse models revealed that depletion of PKC lambda/iota significantly reduces TNBC growth as well as lung metastatic colonization. Furthermore, we have identified a PKC lambda/iota-regulated gene signature consisting of 110 genes, which are significantly associated with indolent to invasive progression of human breast cancer and poor prognosis. Mechanistically, cytokines such as TGF beta and IL1 beta could activate PKC lambda/iota signaling in TNBC cells and depletion of PKC lambda/iota impairs NF-kappa B p65 (RelA) nuclear localization. We observed that cytokine-PKC lambda/iota-RelA signaling axis, at least in part, involved in modulating gene expression to regulate invasion of TNBC cells. Overall, our results indicate that induction and activation of PKC lambda/iota promote TNBC growth, invasion and metastasis. Thus, targeting PKC lambda/iota signaling could be a therapeutic option for breast cancer, including the TNBC subtype.