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, 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.
1] The University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS, USA [2] Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
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Paul
Department of Physiology, University of Kansas Medical Center, Kansas City, KS, USA.
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Gunewardena
1] The University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS, USA [2] Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
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0000000183225886
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Stecklein
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
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Saha
The University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS, USA.
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Parelkar
1] The University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS, USA [2] Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
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Danley
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
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Rajendran
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
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Home
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
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Ray
The University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS, USA.
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Jokar
Department of Urology, University of Kansas Medical Center, Kansas City, KS, USA.
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Vielhauer
1] The University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS, USA [2] Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
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Jensen
1] The University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS, USA [2] Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
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Tawfik
1] The University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS, USA [2] Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
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Paul
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D000099293:Protein Kinase C-lambda; D000099221:Protein Kinase C zeta
D007527:Isoenzymes; D011493:Protein Kinase C; D000099293:Protein Kinase C-lambda; D000099221:Protein Kinase C zeta