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

• Published in: Cell death and differentiation Vol. 21; no. 9; pp. 1469 - 1481
• Main Authors: Paul, A, Gunewardena, S, Stecklein, S R, Saha, B, Parelkar, N, Danley, M, Rajendran, G, Home, P, Ray, S, Jokar, I, Vielhauer, G A, Jensen, R A, Tawfik, O, Paul, S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02-05-2014; Nature Publishing Group
• Subjects: 631/67/1347; 631/67/322; 631/80/86; Animals; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Cell Line, Tumor; Cell Proliferation; Female; Humans; Isoenzymes - genetics; Isoenzymes - metabolism; Life Sciences; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lung Neoplasms - secondary; Mice; Mice, Inbred NOD; Mice, Nude; Mice, SCID; Neoplasm Transplantation; Original Paper; Protein Kinase C - genetics; Protein Kinase C - metabolism; Signal Transduction; Stem Cells; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2014.62

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
λ
/
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 PKC
λ
/
ι
signaling as a potential therapeutic target for TNBC. Our observations indicated that PKC
λ
/
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 PKC
λ
/
ι
expression and activation. Functional analysis in experimental mouse models revealed that depletion of PKC
λ
/
ι
significantly reduces TNBC growth as well as lung metastatic colonization. Furthermore, we have identified a PKC
λ
/
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 TGF
β
and IL1
β
could activate PKC
λ
/
ι
signaling in TNBC cells and depletion of PKC
λ
/
ι
impairs NF-
κ
B p65 (RelA) nuclear localization. We observed that cytokine-PKC
λ
/
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 PKC
λ
/
ι
promote TNBC growth, invasion and metastasis. Thus, targeting PKC
λ
/
ι
signaling could be a therapeutic option for breast cancer, including the TNBC subtype.