A functional Notch–survivin gene signature in basal breast cancer

Lee, Connie Wing-Ching; Simin, Karl; Liu, Qin; Plescia, Janet; Guha, Minakshi; Khan, Ashraf; Hsieh, Chung‐Cheng; Altieri, Dario C.

doi:10.1186/bcr2200

Cited by 109 publications

(104 citation statements)

References 62 publications

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“…Immunohistochemical (IHC) assays were performed as we have described previously, with slight modifications. 16,31 Briefly, adjacent sections were examined for both CD44 and SVV expression using mouse anti-human CD44 antibody (1:100 dilution; R&D) and rabbit polyclonal anti-SVV antibody (1:100 dilution; Santa Cruz Biotechnology) after antigen retrieval performed by boiling the samples in 500 mL of 9 mmol/L citrate buffer (pH 6) (Invitrogen) for 25 minutes. Staining was performed using the Ventana Nexus immunostainer and Ventana detection kit system (Ventana Medical Systems, Inc., Tucson, AZ).…”

Section: Ihcmentioning

confidence: 99%

Survivin Is a Novel Target of CD44-Promoted Breast Tumor Invasion

Abdraboh

Gaur

Hollenbach

et al. 2011

The American Journal of Pathology

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The hyaluronan (HA) receptor CD44 plays an essential role in cell-cell or cell-extracellular matrix communications and is a bioactive signal transmitter. Although a number of studies have described the function of CD44 in breast cancer (BC) metastasis, the underlying mechanisms have yet to be determined. By using a validated tetracycline-off-regulated CD44 expression system in the MCF-7 cell line combined with microarray analysis, we identified survivin (SVV) as a potential downstream transcriptional target of CD44. To test the hypothesis that SVV underpins CD44-promoted BC cell invasion, we combined molecular and pharmacologic approaches and showed that CD44 induction increased SVV expression levels, which in turn promotes BC cell invasion. Further, clinical analysis of breast tissue samples showed that SVV expression patterns paralleled those of the standard form of CD44 during breast tumor progression. More interestingly, we identified the PI3K/E2F1 pathway as a potential molecular link between HA/CD44 activation and SVV transcription. In addition to identifying SVV as a target for HA/CD44 signaling, this investigation provides a better understanding of the molecular mechanisms that underpin the novel function of SVV in breast cancer metastasis. Breast cancer (BC) is the most common cancer and the second most common cause of cancer-related deaths in women in the United States, with more than 175,000 women being diagnosed annually. 1,2 In the later stages of progression, BC cells metastasize from the original tumor site and travel through the vasculature to distant organs such as liver, lungs, brain, and bone. [2][3][4][5] Although the involvement of cell adhesion molecules in cancer development, progression, and metastasis has been established and discussed extensively in the literature, the mechanisms underlying their implication is still nascent. 6 -9 The hyaluronan (HA) receptor CD44, a multistructural and multifunctional cell adhesion molecule involved in cell-cell and cell-extracellular matrix interactions, functions as a bioactive signaling transmitter involved in a variety of cellular responses, including lymphocyte homing, hematopoiesis, inflammation, tumorigenesis, angiogenesis, and metastasis. 10 -13 The CD44 -HA complex initiates a series of intracellular signaling events that lead to migration, adhesion, invasion, proliferation, and differentiation of a variety of cells. The transduction of HA/CD44 signaling can occur through various mechanisms including the following: i) HA binding to CD44 can initiate the extracellular clustering of CD44, resulting in the activation of downstream kinases, 14 ii) CD44 can serve as a co-receptor physically associated with other cell signaling receptors, [15][16][17][18] iii) CD44 can serve as a docking protein for pericellular or cytoplasmic proteins, 19,20 and iv) the transmembrane domain of CD44 can be cleaved, allowing the translocation of the cytoplasmic domain to the nucleus, where it functions as a transcription factor regulating the expression of target gen...

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Section: Ihcmentioning

confidence: 99%

Survivin Is a Novel Target of CD44-Promoted Breast Tumor Invasion

Abdraboh

Gaur

Hollenbach

et al. 2011

The American Journal of Pathology

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“…These human tumors are characterized by high number of CK5-and CK14-positive cells, early loss of p53 and PTEN expression, activated PI3K pathway, resistance to apoptosis, high Notch and c-myc levels, and loss of estrogen receptors (Sorlie et al, 2001;Lee et al, 2008;Marty et al, 2008;Saal et al, 2008;Gusterson, 2009 (Saal et al, 2008), and as enhanced Notch expression also appears to be the hallmark of these tumors (Lee et al, 2008), the MMTV/ N1 IC Tg mice may represent a valid model for this human disease. In human, early events in life, at a time when expansion of stem/progenitor cells occurs, have also long been known to represent major predisposing factors for breast cancer (Michels and Willett, 2004).…”

Section: Discussionmentioning

confidence: 99%

Notch1-induced mammary tumor development is cyclin D1-dependent and correlates with expansion of pre-malignant multipotent duct-limited progenitors

2010

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Members of the Notch family are involved in the development of breast cancer in animal models and in humans. In young transgenic mice, expressing intracellular activated Notch1 (N1 IC ) in mammary cells, we found that CD24 þ CD29 high progenitor cells had enhanced survival, and were expanded through a cyclin D1-dependent pathway. This expansion positively correlated with the later cyclin D1-dependent formation of basal-like ductal tumors. This expanded population exhibited abnormal differentiation skewed toward the basal cells, showed signs of pre-malignancy (low PTEN/p53 and high c-myc) and contained stem cells with impaired selfrenewal in vivo, and more numerous multipotent, ductalrestricted progenitors. Our data suggest that N1 IC can favor transformation of progenitor cells early in life through a cyclin D1-dependent pathway.

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“…JAG1/Notch signaling is a mediator of cancer progression and metastasis, which is associated with the basal-like cancer subtype (17). Therefore, the components of the Notch 1 pathway are attractive therapeutic targets for this cancer subtype.…”

Section: Discussionmentioning

confidence: 99%

“…JAG1/Notch signaling has been considered to be a mediator of cancer progression and metastasis associated with the basal-like subtype (17,18). The majority of lung cancer patients have basal-like disease, and despite initial responses to systemic cytotoxic chemotherapy, the disease follows an aggressive clinical course with early recurrence (19).…”

Section: Introductionmentioning

confidence: 99%

“…To the best of our knowledge, no studies with regard to the correlation between cell-autonomous activation of Notch and TRB3 expression in lung cancer have been published to date. Furthermore, the loss of NUMB expression in breast cancer may contribute to increased Notch activity and Notch-dependent proliferation (15,16).JAG1/Notch signaling has been considered to be a mediator of cancer progression and metastasis associated with the basal-like subtype (17,18). The majority of lung cancer patients have basal-like disease, and despite initial responses to systemic cytotoxic chemotherapy, the disease follows an aggressive clinical course with early recurrence (19).…”

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confidence: 99%

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Knockdown of TRB3 induces apoptosis in human lung adenocarcinoma cells through regulation of Notch 1 expression

Zhou

Luo

Chen

et al. 2013

Molecular Medicine Reports

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Abstract. The upregulation of tribbles homolog 3 (TRB3), a pseudokinase in mammals, has been observed in several types of malignant cancer, including thyroid, ovarian, liver and colorectal cancer. However, the pathological role and the regulatory mechanism of TRB3 in cancer remain unknown. In the current study, we demonstrated that the expression of TRB3 was upregulated in non-small cell lung cancer (NSCLC), correlating with tumor metastasis, disease recurrence and poor survival in patients. Knocking down TRB3 in aggressive lung cancer cell lines was demonstrated to significantly inhibit their malignant behaviors, including in vitro invasion and cell proliferation, as well as in vivo metastasis and tumor growth. The correlation between TRB3 and Notch 1 expression revealed that Notch 1 was downregulated by the knockdown of TRB3 in the lung adenocarcinoma cell lines. These results have provided insights into the correlation between TRB3 expression and lung cancer progression, and thus may have potential for the prognosis and therapy of lung cancer. IntroductionTribbles homolog 3 (TRB3), a pseudokinase, is essential for the catalytic activity that is performed by 10% of the kinase superfamily members (1). TRB3 was also demonstrated to be a key factor in complementary kinome small interfering-RNA (siRNA) function, as a regulator of mitogen-activated protein kinase (MAPK) signaling (2). Previous studies have demonstrated that this occurs through the control of the MAPK-extracellular signal-related kinase (MAPK-ERK) and transforming growth factor β (TGFβ) pathways.Furthermore, TRB3 regulates JAG1 expression and is required for the proliferation of breast cancer cells (3). In addition, TRB3 is required in normal tissues during conditions of hypoxic/endoplasmic reticulum stress or nutrient deprivation, as it is upregulated and counteracts the effects of stress (4,5). TRB3 is also upregulated in cancer as a response to hypoxia (4,6) and is associated with a poor outcome (7) as it promotes the activation of key cancer signaling pathways (such as MAPK-ERK, TGFβ and jagged 1 protein (JAG1)/Notch). TRB3 expression and molecular function has rarely been demonstrated in cancer cell lines, with the exception of breast cancer cell lines (2).The most understood function of the Notch family is cell fate regulation. This function has been regarded to be linked to the homeostasis of stem cell compartments (8-11) and thus, Notch signaling has been implicated in human cancer (10). Cell-autonomous oncogenic activation of Notch was identified in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL). Notch 1 may be activated through chromosomal translocations and/or mutations (10,12). Downregulated expression of Notch-related factors, including Notch receptors, ligands and targets, has also been observed in solid tumors (10,13), including breast (13) and lung (14) cancer. To the best of our knowledge, no studies with regard to the correlation between cell-autonomous activation of Notch and TRB3 expression in lung cancer have been publishe...

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A functional Notch–survivin gene signature in basal breast cancer

Cited by 109 publications

References 62 publications

Survivin Is a Novel Target of CD44-Promoted Breast Tumor Invasion

Survivin Is a Novel Target of CD44-Promoted Breast Tumor Invasion

Notch1-induced mammary tumor development is cyclin D1-dependent and correlates with expansion of pre-malignant multipotent duct-limited progenitors

Knockdown of TRB3 induces apoptosis in human lung adenocarcinoma cells through regulation of Notch 1 expression

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