Cytokines driving breast cancer stemness

Chin, Andrew R.; Wang, Shizhen Emily

doi:10.1016/j.mce.2013.03.024

Cited by 63 publications

(40 citation statements)

References 57 publications

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“…5C, left and right), indicating that MUC1-C induces NF-κB activity and thereby anchorage-independent growth. With regard to downstream signaling, NF-κB has been shown to confer stemness and the formation of spheres by upregulating expression of IL-8 [32, 33]. In this context, we observed marked increases in IL-8 mRNA levels in MCF-7/MUC1-C, as compared to MCF-7/vector, cells (Fig.…”

Section: Resultsmentioning

confidence: 64%

Targeting the MUC1-C oncoprotein inhibits self-renewal capacity of breast cancer cells

et al. 2014

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The capacity of breast cancer cells to form mammospheres in non-adherent serum-free culture is used as a functional characteristic of the self-renewing stem-like cell population. The present studies demonstrate that silencing expression of the MUC1-C oncoprotein inhibits growth of luminal MCF-7 and HER2-overexpressing SKBR3 breast cancer cells as mammospheres. We also show that triple-negative MDA-MB-468 breast cancer cells are dependent on MUC1-C for growth as mammospheres and tumor xenografts. Similar results were obtained when MUC1-C function was inhibited by expression of a MUC1-C(CQC→AQA) mutant. Moreover, treatment with the MUC1-C inhibitor GO-203, a cell penetrating peptide that binds to the MUC1-C cytoplasmic domain and blocks MUC1-C function, confirmed the importance of this target for self-renewal. The mechanistic basis for these findings is supported by the demonstration that MUC1-C activates NF-κB, occupies the IL-8 promoter with NF-κB, and induces IL-8 transcription. MUC1-C also induces NF-κB-dependent expression of the IL-8 receptor, CXCR1. In concert with these results, targeting MUC1-C with GO-203 suppresses IL-8/CXCR1 expression and disrupts the formation of established mammospheres. Our findings indicate that MUC1-C contributes to the self-renewal of breast cancer cells by activating the NF-κB→IL-8/CXCR1 pathway and that targeting MUC1-C represents a potential approach for the treatment of this population.

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Section: Resultsmentioning

confidence: 64%

Targeting the MUC1-C oncoprotein inhibits self-renewal capacity of breast cancer cells

et al. 2014

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“…Despite wide interest in the development of novel diagnostic biomarkers for breast cancer (8,10,20), limited data have been collected regarding whether IL-10, IL-17A and TGF-α levels are associated with the clinical stage of breast cancer, as well as ER, PR and HER2 status. The results of the present study revealed that elevated serum levels of IL-10, IL-17A and TGF-α are strongly associated with ductal carcinoma and are associated with a more severe clinical stage of this disease.…”

Section: Discussionmentioning

confidence: 99%

“…Cells involved in the inflammatory response are attracted by cytokines and chemokines and may promote the onset and progression of breast diseases (4)(5)(6)(7). Inflammation mediates the initiation and growth of breast cancer and cytokines serve a very important role during this process (5,8).…”

Section: Introductionmentioning

confidence: 99%

Association of serum interleukin‑10, interleukin‑17A and transforming growth factor‑α levels with human benign and malignant breast diseases

Liu

Shen

et al. 2018

Exp Ther Med

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Abstract. Interleukin-10 (IL-10), interleukin-17A (IL-17A) and transforming growth factor α (TGF-α) have been implicated in the progression of breast cancer. However, the diagnostic and prognostic roles of these cytokines in ductal carcinoma remain unclear. The present study therefore aimed to determine the serum levels of IL-10, IL-17 and TGF-α in subjects with benign and malignant breast diseases and to evaluate the clinical significance of these cytokines in ductal carcinoma. Pre-operative serum samples were collected from 378 patients with breast disease and 70 healthy subjects. IL-10, IL-17A and TGF-α levels were measured using ELISA. Serum levels of these cytokine in patients with different breast diseases were evaluated. Furthermore, correlations between levels of these cytokines and the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) in ductal carcinoma were determined. The results demonstrated that serum levels of IL-10 and IL-17A were significantly increased in subjects with atypical hyperplasia and ductal carcinoma. Furthermore, IL-10 and IL-17A levels were increased in patients with a more serious clinical tumor stage and tumors that were ER -and PR -. Furthermore, high serum levels of TGF-α were associated with HER2 + tumors. A strong positive correlation was identified between TGF-α and IL-17A levels. Therefore, the results of the current study revealed that elevated serum IL-10, IL-17A and TGF-α levels are strongly associated with ductal carcinoma, specifically with tumor stage. High serum levels of IL-10 and IL-17A were also associated with the negative expression of ER and PR in ductal carcinoma, and high serum levels of TGF-α were associated with the positive expression of HER2 in ductal carcinoma. Thus, serum cytokine levels may be measured to identify patients with a poor prognosis who may benefit from more aggressive management and treatment.

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“…In addition, p38 and Ubc13 control expression of IL-6 mRNA in BCa cells. Previous studies have shown that autocrine IL-6 signaling controls cancer cell growth, cancer stem cell (CSC) renewal, and metastasis (59)(60)(61). IL-6 can stimulate Notch3-dependent up-regulation of Jagged-1 to promote BCa cell growth and maintain an aggressive phenotype (62).…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin-conjugating enzyme Ubc13 controls breast cancer metastasis through a TAK1-p38 MAP kinase cascade

Zhang

Font-Burgada

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Metastatic spread is the leading cause of cancer mortality. Breast cancer (BCa) metastatic recurrence can happen years after removal of the primary tumor. Here we show that Ubc13, an E2 enzyme that catalyzes K63-linked protein polyubiquitination, is largely dispensable for primary mammary tumor growth but is required for metastatic spread and lung colonization by BCa cells. Loss of Ubc13 inhibited BCa growth and survival only at metastatic sites. Ubc13 was dispensable for transforming growth factor β (TGFβ)-induced SMAD activation but was required for activation of non-SMAD signaling via TGFβ-activating kinase 1 (TAK1) and p38, whose activity controls expression of numerous metastasis promoting genes. p38 activation restored metastatic activity to Ubc13-deficient cells, and its pharmacological inhibition attenuated BCa metastasis in mice, suggesting it is a therapeutic option for metastatic BCa.ubiquitination-mediated signaling | pre-clinical studies B reast cancer (BCa) is the leading invasive cancer among women worldwide. BCa-related mortality is usually caused by distant metastases rather than primary tumors (1, 2). The spread of cancer cells from primary tumors to distant organs, termed metastasis, is a multistep process in which cancer cells must (i) invade through the extracellular matrix (ECM), (ii) disseminate into the bloodstream, (iii) survive in the circulation, and (iv) extravasate and successfully colonize distant sites (3). Conventional therapeutic strategies have limited success in preventing and treating metastatic cancer, and BCa metastases can recur many years after removal of the primary tumor. This phenomenon could be due to the complex nature of metastasis itself, and, more realistically, the limitation of current treatments that are effective against primary BCa, i.e., surgical removal and localized radiotherapy, but do little to prevent metastatic recurrence. Even chemotherapy is not very effective against metastatic tumors (4). Unfortunately, the pharmaceutical industry has been reluctant to conduct metastasis prevention trials on patients with early stage cancer using survival and reduction of metastatic load as end points, because such studies are lengthy and require a large number of patients with otherwise relatively good survival prospects (4). Consequently, the development of agents that prevent metastasis from occurring and trigger regression of established metastatic lesions is an urgent unmet need.It was reported that expression of the ubiquitin conjugating enzyme (E2) Ubc13 is up-regulated in metastatic BCa (5). Ubc13, which heterodimerizes with Uev1a, catalyzes formation of lysine 63 (K63)-linked polyubiquitin chains, which control protein-protein interactions involved in DNA damage repair and protein kinase activation (6, 7). In certain immune cells, Ubc13 is required for IκB kinase (IKK)-nuclear factor κB (NF-κB) activation, but a more ubiquitous role for Ubc13 was observed in the activation of MAPK signaling (8-11). We found that Ubc13 is required for activation of mitogen-a...

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Cytokines driving breast cancer stemness

Cited by 63 publications

References 57 publications

Targeting the MUC1-C oncoprotein inhibits self-renewal capacity of breast cancer cells

Targeting the MUC1-C oncoprotein inhibits self-renewal capacity of breast cancer cells

Association of serum interleukin‑10, interleukin‑17A and transforming growth factor‑α levels with human benign and malignant breast diseases

Ubiquitin-conjugating enzyme Ubc13 controls breast cancer metastasis through a TAK1-p38 MAP kinase cascade

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