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, PKCλ/ι, 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 PKCλ/ι signaling as a potential therapeutic target for TNBC. Our observations indicated that PKCλ/ι 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 PKCλ/ι expression and activation. Functional analysis in experimental mouse models revealed that depletion of PKCλ/ι significantly reduces TNBC growth as well as lung metastatic colonization. Furthermore, we have identified a PKCλ/ι-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 TGFβ and IL1β could activate PKCλ/ι signaling in TNBC cells and depletion of PKCλ/ι impairs NF-κB p65 (RelA) nuclear localization. We observed that
cytokine-PKCλ/ι-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 PKCλ/ι promote TNBC growth, invasion and
metastasis. Thus, targeting PKCλ/ι signaling could be a therapeutic option for
breast cancer, including the TNBC subtype.