STAT3 mediates resistance of CD44+CD24-/low breast cancer stem cells to tamoxifen in vitro

Wang, Xiaoyan; Wang, Guozhu; Zhao, Yi; Li, Xiaoan; Ding, Qiang; Shi, Jingping; Ding, Yin; Wang, Shui

doi:10.7555/jbr.26.20110050

Cited by 53 publications

(51 citation statements)

References 40 publications

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“…Furthermore, c-Src is reported to be a common oncogenic driver of variable trastuzumab resistance pathways, implying that suppressing its activity may overcome resistance (40). Similarly, STAT3 plays an essential role in breast cancer stem cells, being correlated with tamoxifen resistance (41). Hence, treatment strategies for suppressing the c-Src/STAT3 interplay are of relevance in treating human breast cancer (14).…”

Section: Discussionmentioning

confidence: 99%

Long-Chain Fatty Acid Analogues Suppress Breast Tumorigenesis and Progression

et al. 2014

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Obesity and type 2 diabetes (T2D) are associated with increased breast cancer incidence and mortality, whereas carbohydrate-restricted ketogenic diets ameliorate T2D and suppress breast cancer. These observations suggest an inherent efficacy of nonesterified long-chain fatty acids (LCFA) in suppressing T2D and breast tumorigenesis. In this study, we investigated novel antidiabetic MEDICA analogues consisting of methyl-substituted LCFA that are neither b-oxidized nor esterified to generate lipids, prompting interest in their potential efficacy as antitumor agents in the context of breast cancer. In the MMTV-PyMT oncomouse model of breast cancer, in which we confirmed that tumor growth could be suppressed by a carbohydraterestricted ketogenic diet, MEDICA treatment suppressed tumor growth, and lung metastasis, promoting a differentiated phenotype while suppressing mesenchymal markers. In human breast cancer cells, MEDICA treatment attenuated signaling through the STAT3 and c-Src transduction pathways. Mechanistic investigations suggested that MEDICA suppressed c-Src-transforming activity by elevating reactive oxygen species production, resulting in c-Src oxidation and oligomerization. Our findings suggest that MEDICA analogues may offer therapeutic potential in breast cancer and overcome the poor compliance of patients to dietary carbohydrate restriction. Cancer Res; 74(23); 6991-7002. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

Long-Chain Fatty Acid Analogues Suppress Breast Tumorigenesis and Progression

et al. 2014

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“…It’s possible that the presence of cancer stem cell confers a drugs resistance. In vitro studies documented that cancer stem cell exert antiapoptotic effect on breast cancer cells and counteract cell-cycle changes caused by tamoxifen, so promoting tumor growth and invasiveness (Wang et al 2012b; Lin et al 2013). …”

Section: New Stem Cell Therapies and Surgical Breast Cancer Reconstrumentioning

confidence: 99%

Adult adipose-derived stem cells and breast cancer: a controversial relationship

et al. 2014

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Breast cancer is the most common cancer in women and autologous fat grafting is an important clinical application in treatment of post-surgical deformities. The simplicity of fat grafting procedures and the absence of subsequent visible scar prompted an increasing interest for this technique. The plasticity of adipose-derived stem cells (ASCs) obtained from stromal vascular fraction (SVF) of adult adipose tissue provided exciting perspectives for regenerative medicine and surgery. The recent discovery that SVF/ASC enrichment further ameliorates clinical efficacy of grafting ASCs suggest as ASC-mediated new adipogenesis and vasculogenesis. ASC adipogenic differentiation involves Akt activity and EGFRs, FGFRs, ERbB2 receptor-mediated pathways that also play a pivotal role in the regulation of breast cancer growth. Moreover, the finding that platelet-derived growth factors and hormones improved long-term maintenance of fat grafting raises new concerns for their use during breast reconstruction after cancer surgery. However, it remains unclear whether grafted or resident ASCs may increase the risk of de novo cancer development or recurrence. Preliminary follow-up studies seem to support the efficacy and safety of SVF/ASCs enrichment and the additional benefit from the combined use of autologous platelet-derived growth factors and hormones during breast reconstruction procedures. In the present review we highlighted the complex interplay between resident or grafted ASCs, mature adipocytes, dormant or active breast cancer cells and tumor microenvironment. Actually, data concerning the permissive role of ASCs on breast cancer progression are contrasting, although no clear evidence speaking against their use exists.

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“…A mutated STAT3 protein that does not require phosphorylation before dimerisation can impart tumourigenicity to transformed fibroblasts. Furthermore, IL-6-mediated protection against drug-induced apoptosis in human neuroblastoma cells also depends upon STAT3 activation (Ara et al, 2013); and STAT3 may partially mediate tamoxifen resistance in CD44 + / CD24 2/low MCF-7 breast cancer stem cells (Wang et al, 2012). Interestingly, unphosphorylated STAT3 too, appears to inhibit proapoptotic genes in certain cancer cell lines, but not in untransformed cells.…”

Section: Stat3 As An Oncogenementioning

confidence: 99%

Role of the JAK‐STAT Signalling Pathway in Cancer

Dutta

2013

Encyclopedia of Life Sciences

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The JAK‐STAT pathway is important in cytokine‐mediated immune responses. Research in the JAK/STAT field has elucidated its roles in various cellular processes such as proliferation, apoptosis and migration, and has found frequent dysregulation of the JAK/STAT pathway in diverse types of cancer. In recent years, JAK and STAT have also been implicated in a noncanonical mode of action: the regulation of genomic stability independent of their functions in cytokine signalling. Research in Drosophila has shown that nuclear, unphosphorylated STAT physically interacts with heterochromatin protein 1 (HP1) and stabilises its binding to heterochromatin. A similar interaction occurs in human cells, where unphosphorylated STAT5A interacts with HP1α and acts as a tumour suppressor. Nuclear JAK2, however, functions as a histone tyrosine kinase, displacing HP1α from chromatin. These data have important implications for human cancer: They suggest new drug therapies, which could target the noncanonical functions of JAK and STAT. In this article, we discuss how the canonical arm of the JAK‐STAT pathway functions in tumourigenesis, focussing on JAK and on STAT1, STAT3 and STAT5. We then discuss recent findings regarding epigenetic silencing of JAK/STAT pathway components, and the direct involvement of JAK and STAT in regulating heterochromatin integrity. Key Concepts: The tyrosine kinase JAK and its downstream target STAT respond to cytokine signalling in cells. In response to cytokines, JAK itself is phosphorylated, leading to its activation. The activated JAK kinase then phosphorylates specific STATs. STAT proteins dimerise and translocate into the nucleus upon phosphorylation by JAK, where they bind to DNA and regulate transcription. Overactivation of the JAK‐STAT pathway can cause cancer by bypassing apoptosis and cell cycle checkpoints. Unphosphorylated STAT is also found in the nuclei and mitochondria of cells that are not stimulated by cytokines. Mitochondrial STAT upregulates cellular respiration and can promote oncogenic transformation. Unphosphorylated nuclear STAT binds to HP1α and stabilises heterochromatin. STAT5A in colon cancer cells acts as a tumour suppressor via this mechanism. Nuclear JAK2 is a histone tyrosine kinase. Phosphorylation of histone 3 tyrosine 41 displaces HP1α/CBX5 from chromatin and contributes to tumourigenicity. In some cancers, DNA methylation suppresses the expression of inhibitory SOCS proteins, resulting in uncontrolled JAK/STAT pathway activation.

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STAT3 mediates resistance of CD44+CD24-/low breast cancer stem cells to tamoxifen in vitro

Cited by 53 publications

References 40 publications

Long-Chain Fatty Acid Analogues Suppress Breast Tumorigenesis and Progression

Long-Chain Fatty Acid Analogues Suppress Breast Tumorigenesis and Progression

Adult adipose-derived stem cells and breast cancer: a controversial relationship

Role of the JAK‐STAT Signalling Pathway in Cancer

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