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

Abstract

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, PKCk/i, 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 PKCk/i signaling as a potential therapeutic target for TNBC. Our observations indicated that PKCk/i 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 PKCk/i expression and activation. Functional analysis in experimental mouse models revealed that depletion of PKCk/i significantly reduces TNBC growth as well as lung metastatic colonization. Furthermore, we have identified a PKCk/i-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 TGFb and IL1b could activate PKCk/i signaling in TNBC cells and depletion of PKCk/i impairs NF-jB p65 (RelA) nuclear localization. We observed that cytokine-PKCk/i-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 PKCk/i promote TNBC growth, invasion and metastasis. Thus, targeting PKCk/i signaling could be a therapeutic option for breast cancer, including the TNBC subtype.

Glutathione S‐transferase omega 1 inhibition activates JNK‐mediated apoptotic response in breast cancer stem cells

“…Luminal‐type breast cancer patients express estrogen, progesterone and HER2 receptors on the cancer cells and respond to endocrine and HER2 targeted therapies, respectively . Basal‐type breast cancer is the most aggressive phenotype, in which cancer cells lack expression of these receptors (triple negative) and therefore patients do not respond to endocrine, chemo‐ and radiation therapies . A recent report suggests that triple negative breast cancers (TNBCs) develop chemoresistance within a few years of initial treatment .…”

A 3q gene signature associated with triple negative breast cancer organ specific metastasis and response to neoadjuvant chemotherapy

“…A recent study specifically demonstrated that PRKCI signaling promotes TNBC cell growth and metastasis through NF-κB pathway which could be regulated by TGFβ and IL1β25. We previously reported a new oncogenic role for RNA binding protein FXR1 linking to PRKCI and ECT2 in NSCLC9.…”

“…Moreover, none of our 3q 19 genes overlaps with known gene signatures tested in this study, arguing a lack of efficacy of using these known gene signatures as prognostic factors in TNBC patients. Although the exact role of these 19 genes in breast cancer metastasis is unclear, 12 genes including FXR1 have been studied functionally or mechanistically in human cancers including lung and breast (Supplemental Table 21)919202122232425. For instance, PIK3CA is the most well-studied oncogene among our 3q gene signature due to its high mutation rate in human cancer, especially in breast cancer23.…”

Molecular Control of Atypical Protein Kinase C: Tipping the Balance between Self-Renewal and Differentiation

“…It is interesting to note that the aPKC iota/lambda and zeta isoforms may have distinct functions in regulating proliferation based on their requirement in different cell types. For example, the iota/lambda isoform promotes the growth and metastasis of triple-negative breast cancers, a subtype defined by the absence of estrogen receptor, progesterone receptor and epidermal growth factor receptor 2 21 . However, the zeta isoform is required for the mitogen induced growth of squamous cell carcinomas of the head and neck 22 .…”