Notch-1 and Notch-4 Biomarker Expression in Triple-Negative Breast Cancer

Speiser, Jodi; Foreman, Kimberly E.; Drinka, Eva; Godellas, Constantine V.; Perez, Claudia B.; Salhadar, Alia; Erşahin, Çağatay; Rajan, Prabha

doi:10.1177/1066896911427035

Cited by 77 publications

(68 citation statements)

References 26 publications

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“…Tumorigenesis and prognosis of human breast cancer are reportedly influenced by Notch signaling pathway activity [14][15][16]. We observed the same correlation between NIC and H4K16ac in breast cancer tissues as that in HCC (Fig.…”

Section: Activation Of the Notch Pathway Induces A Reduction In H4k16supporting

confidence: 72%

MDM2–MOF–H4K16ac axis contributes to tumorigenesis induced by Notch

et al. 2014

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Identification of the epigenetic mechanisms involved in the transmission of Notch signaling is useful for personalized medicine. We observed that aberrantly high levels of Notch activity resulted in H4K16ac downregulation in hepatocellular carcinoma and breast cancer cell lines and tissues. This downregulated acetylation was a consequence of increased male on the first degradation following the upregulation of full‐length murine double minute 2 in different cancer types. We observed that increases in male on the first could attenuate heterogeneity induced by aberrantly high levels of Notch activity. Our results provide new insights into the analysis and treatment of Notch‐induced hepatocellular carcinoma and breast cancer.

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Section: Activation Of the Notch Pathway Induces A Reduction In H4k16supporting

confidence: 72%

MDM2–MOF–H4K16ac axis contributes to tumorigenesis induced by Notch

et al. 2014

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“…Pharmacologic as well as genetic inhibition of Notch4 decreases stem cell activity in vitro and reduces tumor formation in vivo (33). In addition, Notch4 overexpression has been observed in triple-negative human breast cancer specimens (37). The present study reveals decrease in ALDH1 activity after Notch4 knockdown in MCF-7 cells.…”

Section: Discussionmentioning

confidence: 99%

Mammary Cancer Chemoprevention by Withaferin A Is Accompanied byIn VivoSuppression of Self-Renewal of Cancer Stem Cells

Kim

Singh

2014

Cancer Prevention Research

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Current dogma favors elimination of therapy-resistant cancer stem cells (bCSC) for chemoprevention of breast cancer. We showed recently that mammary cancer development in a transgenic mouse model (mouse mammary tumor virus-neu; MMTV-neu) was inhibited significantly upon treatment with withaferin A (WA), a steroidal lactone derived from a medicinal plant. Herein, we demonstrate that the mammary cancer prevention by WA is accompanied by in vivo suppression of bCSC. In vitro mammosphere formation was dose-dependently inhibited by WA treatment in MCF-7 and SUM159 human breast cancer cells. Other markers of bCSC including aldehyde dehydrogenase 1 (ALDH1) activity and CD44high/CD24low/epithelial specific antigen-positive (ESA+) fraction were also decreased significantly in the presence of plasma achievable doses of WA. On the other hand, WA exposure resulted in cell line-specific changes in Oct4, SOX-2, and Nanog mRNA expression. WA administration to MMTV-neu mice (0.1 mg/mouse, three times/week for 28 weeks) resulted in inhibition of mammosphere number and ALDH1 activity in vivo. Mechanistic studies revealed that while urokinase-type plasminogen activator receptor overexpression conferred partial protection against bCSC inhibition by WA, Notch4 was largely dispensable for this response. WA treatment also resulted in sustained (MCF-7) or transient (SUM159) downregulation of Bmi-1 (B cell-specific Moloney murine leukemia virus insertion region-1) protein. Ectopic expression of Bmi-1 conferred partial but significant protection against ALDH1 activity inhibition by WA. Interestingly, WA treatment caused induction of Kruppel-like factor 4 (KLF4) and its knockdown augmented bCSC inhibition by WA. In conclusion, the present study shows in vivo effectiveness of WA against bCSC.

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“…In line with this notion, TNBC seems to differentially-activate Notch. Indeed, Notch1 and Notch4 are overexpressed in TNBC [12]. Moreover, in contrast to normal and ER+ breast cancer tissues, the activation of Notch in ER– breast cancer is linked to survivin upregulation (an apoptosis inhibitor and cell cycle regulator), which suggests ER- breast cancer cells are dependent on Notch-survivin signaling [13].…”

Section: Introductionmentioning

confidence: 99%

NILCO biomarkers in breast cancer from Chinese patients

et al. 2014

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BackgroundNotch, IL-1 and leptin are known pro-angiogenic factors linked to breast cancer development, tumor aggressiveness and poor prognosis. A complex crosstalk between these molecules (NILCO) has been reported in breast cancer cell lines. However, whether NILCO biomarkers are differentially expressed in estrogen responsive (ER+), unresponsive (ER-) and triple negative (TNBC) breast cancer tissues is unknown.MethodsExpression levels of nine NILCO and targets [Notch1, Notch4, JAG1, DLL4, VEGF, VEGFR2 (FLK-1), leptin, leptin receptor (OB-R) and interleukin-1 receptor type I (IL-1R tI)] were examined via immunohistochemistry in breast cancer tissue microarrays from Chinese patients (ER+, n=33; ER-, n=21; TNBC, n=13) and non-malignant breast tissue (n=5; Pantomics, Inc.) using a semi-quantitative analysis of intensity staining, HSCORE.ResultsCategorical expression of NILCO and targets (+ or -) was similar among all cancer tissues. However, TNBC showed differential localization pattern of NILCO. TNBC showed fewer nuclei and cytoplasms positive for Notch4 and JAG1, but more cytoplasms positive for leptin. In addition, fewer TNBC stromas were positive for Notch1 and Notch4, but 100% of TNBC stromas were positive for VEGFR2. Moreover, TNBC had lower DLL4 and IL-1R tI expression. TNBC and ER- showed higher expression of EGFR, but lower expression of AR. Leptin and OB-R were detected in more than 61% of samples. Leptin positively correlated to OB-R, JAG1, VEGF, and marginally to IL-1R tI. Notch1 positively correlated to IL-1R tI. EGFR and Ki67 were positively associated to Notch1, but no associations of NILCO and targets with p53 were found.ConclusionsPresent data suggest that NILCO components are differentially expressed in breast cancer. TNBC showed distinctive patterns for NILCO expression and localization. The complex crosstalk between leptin, IL-1 and Notch could differentially drive breast cancer growth and angiogenesis. Furthermore, the analysis of NILCO and targets using Pathway Studio9 software (Ariadine Genomics) showed multiple molecular relationships that suggest NILCO has potential prognostic biomarker value in breast cancer.

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Notch-1 and Notch-4 Biomarker Expression in Triple-Negative Breast Cancer

Cited by 77 publications

References 26 publications

MDM2–MOF–H4K16ac axis contributes to tumorigenesis induced by Notch

MDM2–MOF–H4K16ac axis contributes to tumorigenesis induced by Notch

Mammary Cancer Chemoprevention by Withaferin A Is Accompanied byIn VivoSuppression of Self-Renewal of Cancer Stem Cells

NILCO biomarkers in breast cancer from Chinese patients

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