Pluripotent Stem Cell miRNAs and Metastasis in Invasive Breast Cancer

Volinia, Stefano; Nuovo, Gerard J.; Drusco, Alessandra; Costinean, Stefan; Abujarour, Ramzey; Desponts, Caroline; Garofalo, Michela; Baffa, Raffaele; Aeqilan, Rami; Maharry, Kati; Garzon, Maria Elena Sana Ramiro; Leva, Gianpiero Di; Gasparini, Pierluigi; Dama, Paola; Marchesini, Jlenia; Galasso, Marco; Manfrini, Marco; Zerbinati, Carlotta; Corrà, Fabio; Wise, Timothy F.; Wojcik, Sylwia E.; Previati, Maurizio; Pichiorri, Flavia; Zanesi, Nicola; Alder, Hansjüerg; Palatini, Jeff; Huebner, Kay; Shapiro, Charles L.; Negrini, Massimo; Vecchione, Andrea; Rosenberg, Anne; Croce, Carlo M.

doi:10.1093/jnci/dju324

Cited by 30 publications

(24 citation statements)

References 37 publications

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“…SOX2 is amplified in certain cancers and can drive clonogenic tumor growth (46). Moreover, miR-302b expression in breast cancers was recently associated with expression of stem cell markers, nodal metastasis, and poor patient outcome (47). In ES, Sox2 transactivates OCT4, NANOG, MYC, and KLF4 and these, in turn, transactivate SOX2 (13).…”

Section: Discussionmentioning

confidence: 99%

Interactions between Adipocytes and Breast Cancer Cells Stimulate Cytokine Production and Drive Src/Sox2/miR-302b–Mediated Malignant Progression

et al. 2016

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Consequences of the obesity epidemic on cancer morbidity and mortality are not fully appreciated. Obesity is a risk factor for many cancers, but the mechanisms by which it contributes to cancer development and patient outcome have yet to be fully elucidated. Here, we examined the effects of coculturing humanderived adipocytes with established and primary breast cancer cells on tumorigenic potential. We found that the interaction between adipocytes and cancer cells increased the secretion of proinflammatory cytokines. Prolonged culture of cancer cells with adipocytes or cytokines increased the proportion of mammosphere-forming cells and of cells expressing stem-like markers in vitro. Furthermore, contact with immature adipocytes increased the abundance of cancer cells with tumor-forming and metastatic potential in vivo. Mechanistic investigations demonstrated that cancer cells cultured with immature adipocytes or cytokines activated Src, thus promoting Sox2, c-Myc, and Nanog upregulation. Moreover, Sox2-dependent induction of miR-302b further stimulated cMYC and SOX2 expression and potentiated the cytokine-induced cancer stem cell-like properties. Finally, we found that Src inhibitors decreased cytokine production after coculture, indicating that Src is not only activated by adipocyte or cytokine exposures, but is also required to sustain cytokine induction. These data support a model in which cancer cell invasion into local fat would establish feed-forward loops to activate Src, maintain proinflammatory cytokine production, and increase tumor-initiating cell abundance and metastatic progression. Collectively, our findings reveal new insights underlying increased breast cancer mortality in obese individuals and provide a novel preclinical rationale to test the efficacy of Src inhibitors for breast cancer treatment. Cancer Res; 76(2); 491-504. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 99%

Interactions between Adipocytes and Breast Cancer Cells Stimulate Cytokine Production and Drive Src/Sox2/miR-302b–Mediated Malignant Progression

et al. 2016

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“…miRNAs could negatively regulate EMT‐related genes at the post‐transcriptional level, and play critical roles in cancer metastasis . Previous studies reported that miR‐143 is associated with the regulation of EMT, and miR‐143 is significantly dysregulated in many human tumor types, including prostate cancer, hepatocellular carcinoma, non‐small cell lung cancer, and gastric cancer .…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, a better understanding of the molecular mechanisms underlying EMT is required to facilitate the development of effective therapeutic strategies for breast cancer patients. miRNAs could negatively regulate EMT-related genes at the post-transcriptional level, and play critical roles in cancer metastasis [19,20]. Previous studies reported that miR-143 is associated with the regulation of EMT, and miR-143 is significantly dysregulated in many human tumor types, including prostate cancer, hepatocellular carcinoma, non-small cell lung cancer, and gastric cancer [6,21].…”

Section: Discussionmentioning

confidence: 99%

miR‐143 suppresses epithelial–mesenchymal transition and inhibits tumor growth of breast cancer through down‐regulation of ERK5

Zhai

et al. 2015

Molecular Carcinogenesis

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Epithelial-mesenchymal transition (EMT) plays a pivotal role in the development of cancer invasion and metastasis. Many studies have significantly enhanced the knowledge on EMT through the characterization of microRNAs (miRNAs) influencing the signaling pathways and downstream events that define EMT on a molecular level. In this study, we found that miR-143 suppressed EMT. Up-regulating miR-143 enhanced E-cadherin-mediated cell-cell adhesion ability, reduced mesenchymal markers, and decreased cell proliferation, migration, and invasion in vitro. In vivo, the xenograft mouse model also unveiled the suppressive effects of miR-143 on tumor growth. Additionally, we demonstrated that up-regulating extracellular signal regulated kinase 5 (ERK5) was associated with poor prognosis of breast cancer patients. Moreover, we observed an inverse correlation between miR-143 and ERK5 in breast cancer tissues. miR-143 directly targeted seed sequences in the 3'-untranslated regions of ERK5. Furthermore, we revealed that the downstream molecules of glycogen synthase kinase 3 beta (GSK-3β)/Snail signaling were involved in EMT and modulated by ERK5. In summary, our findings demonstrated that miR-143 down-regulated its target ERK5, leading to the suppression of EMT induced by GSK-3β/Snail signaling of breast cancer. © 2015 Wiley Periodicals, Inc.

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“…MicroRNA can bind to the 3′ terminal untranslation region (3′UTR) of targeted mRNAs to inhibit their translation and to promote their degradation [4–6]. Previous studies have shown that miR-224 can bind to the tumor suppressors of TNFα-induced protein 1 (TNFAIP1) and Smad4, Raf kinase inhibitor protein (RKIP), apoptosis inhibitor-5 (API-5), PH domain leucine-rich-repeat protein phosphatase 1 (PHLPP1), and PHLPP2 to promote the survival and proliferation of colorectal cancer (CRC) and hepatocellular carcinoma (HCC), but bind to the TRIB1 to promote apoptosis of prostatic cancer cells [7–11].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-224 inhibits proliferation and migration of breast cancer cells by down-regulating Frizzled 5 expression

Liu

Shen

et al. 2016

Oncotarget

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The Wnt/β-catenin signaling is crucial for the proliferation and migration of breast cancer cells. However, the expression of microRNA-224 (miR-224) in the different types of breast cancers and its role in the Wnt/β-catenin signaling and the proliferation and migration of breast cancer cells are poorly understood. In this study, the levels of miR-224 in different types of breast cancer tissues and cell lines were examined by quantitative RT-PCR and the potential targets of miR-224 in the Wnt/β-catenin signaling were investigated. The effects of altered miR-224 expression on the frequency of CD44+CD24− cancer stem-like cells (CSC), proliferation and migration of MCF-7 and MDA-MB-231 cells were examined by flow cytometry, MTT and transwell migration. We found that the levels of miR-224 expression in different types of breast cancer tissues and cell lines were associated inversely with aggressiveness of breast cancers. Enhanced miR-224 expression significantly reduced the fizzled 5-regulated luciferase activity in 293T cells, fizzled 5 expression in MCF-7 and MDA-MB-231 cells, the β-dependent luciferase activity in MCF-7 cells, and the nuclear translocation of β-catenin in MDA-MB-231 cells. miR-224 inhibition significantly increased the percentages of CSC in MCF-7 cells and enhanced proliferation and migration of MCF-7 cells. Enhanced miR-224 expression inhibited proliferation and migration of MDA-MB-231 cells, and the growth of implanted breast cancers in vivo. Induction of frizzled 5 over-expression mitigated the miR-224-mediated inhibition of breast cancer cell proliferation. Collectively, these data indicated that miR-224 down-regulated the Wnt/β-catenin signaling possibly by binding to frizzled 5 and inhibited proliferation and migration of breast cancer cells.

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Pluripotent Stem Cell miRNAs and Metastasis in Invasive Breast Cancer

Abstract: In healthy tissues the MIR302(high)/MIR203(low) asymmetry was characteristic of embryonic and induced pluripotency. In invasive ductal carcinoma, the MIR302/MIR203 asymmetry was associated with stem cell markers, metastasis, and shorter survival.

Cited by 30 publications

References 37 publications

Interactions between Adipocytes and Breast Cancer Cells Stimulate Cytokine Production and Drive Src/Sox2/miR-302b–Mediated Malignant Progression

Interactions between Adipocytes and Breast Cancer Cells Stimulate Cytokine Production and Drive Src/Sox2/miR-302b–Mediated Malignant Progression

miR‐143 suppresses epithelial–mesenchymal transition and inhibits tumor growth of breast cancer through down‐regulation of ERK5

MicroRNA-224 inhibits proliferation and migration of breast cancer cells by down-regulating Frizzled 5 expression

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