Protein Kinase C α Is a Central Signaling Node and Therapeutic Target for Breast Cancer Stem Cells

Tam, Wai Leong; Lu, Haihui; Buikhuisen, Joyce Y.; Soh, Boon Seng; Lim, Elgene; Reinhardt, Ferenc; Wu, Zhenhua J.; Krall, Jordan A.; Bierie, Brian; Guo, Wenjun; Chen, Xi; Liu, Xiaole Shirley; Brown, Myles; Lim, Bing; Weinberg, Robert A.

doi:10.1016/j.ccr.2013.08.005

Cited by 291 publications

(317 citation statements)

References 36 publications

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“…Several reports have connected Fra-1/AP-1 in human breast cancer to increased expression of the EMT-TFs Zeb1 and Zeb2 and to a lesser extent Slug. [12][13][14][15]17 We investigated whether Fra-1/AP-1 and the EMT-TFs also correlated in mouse mammary EMT. Expression of Fra-1 in EpH4 cells induced EMT and increased proliferation, migration and invasiveness.…”

Section: Discussionmentioning

confidence: 99%

“…Our findings are consistent with reports that Fra-1 affects the proliferation and motility of human breast cancer cell lines 17,42 and that Fra-1 is a critical EMT effector downstream of Ras signalling. 13,14 Ras and TGFβ cooperate to induce and stabilize a mesenchymal switch in EpH4 cells. 21,22,40 Unlike human breast cancer cells where upstream signalling kinases activation is required, 14,16 ectopic Fra-1 expression was sufficient for EMT and tumorigenesis in EpH4 cells.…”

Section: Discussionmentioning

confidence: 99%

“…10,11 Strikingly, suppression of Fra-1 restores epithelial characteristics, including E-cadherin expression, and abrogates the invasive potential of human breast cancer cell lines. 12,13 Furthermore, Fra-1 has been implicated in human breast cancer EMT through increased expression of the Snai2/Slug, Zinc finger E-box-binding homeobox 1 (Zeb1) and Zeb2 EMT-TFs, [13][14][15][16][17] although the mechanisms how Fra-1 modulates EMT-TFs expression are not fully understood.…”

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Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFβ expression

et al. 2014

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Epithelial-to-mesenchymal transition (EMT) is essential for embryonic morphogenesis and wound healing and critical for tumour cell invasion and dissemination. The AP-1 transcription factor Fra-1 has been implicated in tumorigenesis and in tumour-associated EMT in human breast cancer. We observed a significant inverse correlation between Fra-1 mRNA expression and distant-metastasis-free survival in a large cohort of breast cancer patients derived from multiple array data sets. This unique correlation among Fos genes prompted us to assess the evolutionary conservation between Fra-1 functions in EMT of human and mouse cells. Ectopic expression of Fra-1 in fully polarized, non-tumourigenic, mouse mammary epithelial EpH4 cells induced a mesenchymal phenotype, characterized by a loss of epithelial and gain of mesenchymal markers. Proliferation, motility and invasiveness were also increased in the resulting EpFra1 cells, and the cells were tumourigenic and efficiently colonized the lung upon transplantation. Molecular analyses revealed increased expression of Tgfβ1 and the EMT-inducing transcription factors Zeb1, Zeb2 and Slug. Mechanistically, Fra-1 binds to the tgfb1 and zeb2 promoters and to an evolutionarily conserved region in the first intron of zeb1. Furthermore, increased activity of a zeb2 promoter reporter was detected in EpFra1 cells and shown to depend on AP-1-binding sites. Inhibiting TGFβ signalling in EpFra1 cells moderately increased the expression of epithelial markers, whereas silencing of zeb1 or zeb2 restored the epithelial phenotype and decreased migration in vitro and tumorigenesis in vivo. Thus Fra-1 induces changes in the expression of genes encoding EMT-related transcription factors leading to the acquisition of mesenchymal, invasive and tumorigenic capacities by epithelial cells. This study defines a novel function of Fra-1/AP-1 in modulating tgfb1, zeb1 and zeb2 expression through direct binding to genomic regulatory regions, which establishes a basis for future in vivo genetic manipulations and preclinical studies using mouse models. Epithelial-to-mesenchymal transition (EMT) is a complex biological programme that occurs in physiological processes during embryonic development and wound healing as well as in pathological conditions, such as organ fibrosis and carcinogenesis. During EMT, cells lose epithelial features and acquire mesenchymal characteristics. The acquisition of a mesenchymal state by malignant cancer cells is associated with decreased cell-cell adhesion, and increased migratory and invasive properties, which are crucial for metastasis. [1][2][3][4][5] The adherens junction (AJ) protein E-cadherin, encoded by cdh1, is a central determinant of the epithelial state and its downregulation is the hallmark of EMT. A number of molecular pathways converging on E-cadherin have been implicated in EMT. Transcription factors (TF) of the Snail, Zeb and Twist families, initially identified as regulators of epithelialmesenchymal plasticity during morphogenesis were shown to orchestrate EMT by...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFβ expression

et al. 2014

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“…miR-200b, which is one of the members of the miR-200 family, has also been reported to have abnormal expression in various types of cancer, including bladder cancer and gastric carcinoma (33,34) PKCα belongs to the protein kinase C family and has been indicated to be involved in tumorigenesis, invasion, metastasis and proliferation (35)(36)(37). Previous studies of breast cancer indicated that PKCα could serve as an effective therapeutic target due to its notable mediator role in cancer (38)(39)(40). Furthermore, upregulation of PKCα results in cancer cell invasion and proliferation (36,41,42).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-200b inhibits pituitary tumor cell proliferation and invasion by targeting PKCα

Wang

Yin

Zhao

et al. 2017

Experimental and Therapeutic Medicine

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“…Moreover, elevated MMP2, which is regulated by PKC, is tightly involved in glioma invasion (9). Notably, Tam et al studied the role of PKCα in cancer treatment and reported that it has been a major focus for various types of cancer and even cancer stem cells (28). In addition, Hu et al reported that activation of PKCα is also implicated in glioma cell migration (15).…”

Section: A B Cmentioning

confidence: 99%

Regulation of C6 glioma cell migration by thymol

et al. 2016

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Abstract. Tumor cell motility exhibits a crucial role in tumor development. Therefore, the present study aimed to investigate whether thymol could reduce C6 glioma cell migration. Cell viability was determined using the EZ-Cytox Cell Viability kit. The scratch wound healing and Boyden chamber assays were performed to test C6 glioma cell migration in the presence of fetal bovine serum (FBS). Additionally, the study investigated whether signaling proteins relevant to C6 glioma cell migration, i.e., extracellular signal-regulated kinases (ERK)1/2, protein kinase Cα (PKCα), matrix metallopeptidase (MMP)9 and MMP2, were affected by thymol treatment. Up to 30 µM, thymol did not alter cell viability, whereas 100 µM thymol induced the death of ~20% of the cells. Furthermore, thymol (30 µM) significantly reduced FBS-induced migration. In the FBS-stimulated C6 glioma cells, thymol (30 µM) suppressed PKCα and ERK1/2 phosphorylation. MMP9 and MMP2 production was also significantly reduced by treatment with 30 µM thymol in the C6 glioma cells. Taken together, these results indicate that thymol attenuates C6 glioma cell migration. Additionally, the study suggests that the effect of thymol on the FBS-induced migration of C6 glioma cells affects PKCα and ERK1/2 signaling, and suppresses MMP9 and MMP2 production.

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Protein Kinase C α Is a Central Signaling Node and Therapeutic Target for Breast Cancer Stem Cells

Cited by 291 publications

References 36 publications

Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFβ expression

Fra-1/AP-1 induces EMT in mammary epithelial cells by modulating Zeb1/2 and TGFβ expression

MicroRNA-200b inhibits pituitary tumor cell proliferation and invasion by targeting PKCα

Regulation of C6 glioma cell migration by thymol

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