The nuclear factor kappa B (NF-κB): A potential therapeutic target for estrogen receptor negative breast cancers

Biswas, Debajit K.; Dai, Sun-chun; Cruz, A. Pérez de la; Weiser, Barbara; Graner, Edgard; Pardee, Arthur B.

doi:10.1073/pnas.151257998

Cited by 160 publications

(134 citation statements)

References 38 publications

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“…Cluster analysis and global testing demonstrated that NF-kB hyperactivation was indeed associated with IBC, but, despite this association, NF-kB hyperactivation is not the main causative molecular alteration in IBC, as shown by GSEA. Hence, NF-kB hyperactivation is not specific for IBC, which agrees with previous findings, that NF-kB hyperactivation is implicated in the generation ERnegative breast cancer in general (Biswas et al, 2001;Zhou et al, 2005;Van Laere et al, 2007). One possible explanation for the involvement of NF-kB in ER-negative breast cancer is the hyperactivation of MAP kinases secondary to EGFR and/or ErbB2 overexpression, leading to an NF-kB-dependent downregulation of ER expression (Van Laere et al, 2007).…”

Section: Discussionsupporting

confidence: 90%

Distinct molecular phenotype of inflammatory breast cancer compared to non-inflammatory breast cancer using Affymetrix-based genome-wide gene-expression analysis

et al. 2007

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The present study aims at a platform-independent confirmation of previously obtained cDNA microarray results on inflammatory breast cancer (IBC) using Affymetrix chips. Gene-expression data of 19 IBC and 40 non-IBC specimens were subjected to clustering and principal component analysis. The performance of a previously identified IBC signature was tested using clustering and gene set enrichment analysis. The presence of different cell-of-origin subtypes in IBC was investigated and confirmed using immunohistochemistry on a TMA. Differential gene expression was analysed using SAM and topGO was used to identify the fingerprints of a pro-metastatic-signalling pathway. IBC and non-IBC have distinct gene-expression profiles. The differences in gene expression between IBC and non-IBC are captured within an IBC signature, identified in a platform-independent manner. Part of the gene-expression differences between IBC and non-IBC are attributable to the differential presence of the cell-of-origin subtypes, since IBC primarily segregated into the basal-like or ErbB2-overexpressing group. Strikingly, IBC tumour samples more closely resemble the gene-expression profile of T1/T2 tumours than the gene-expression profile or T3/T4 tumours. We identified the insulin-like growth factor-signalling pathway, potentially contributing to the biology of IBC. Our previous results have been validated in a platform-independent manner. The distinct biological behaviour of IBC is reflected in a distinct gene-expression profile. The fact that IBC tumours are quickly arising tumours might explain the close resemblance of the IBC gene-expression profile to the expression profile of T1/T2 tumours.

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Section: Discussionsupporting

confidence: 90%

Distinct molecular phenotype of inflammatory breast cancer compared to non-inflammatory breast cancer using Affymetrix-based genome-wide gene-expression analysis

et al. 2007

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“…These reports together with the observed upregulation of IkBa in prostate cancer cells may provide a mechanism to explain the increased apoptosis and reduced tumour vascularity in prostate cancer specimens (Keledjian et al, 2001). Constitutive activation of NF-kB has been reported in many tumours (Baldwin, 1996), including androgen-independent prostate cancer cells (Pajonk et al, 1999;Palayoor et al, 1999;Suh et al, 2002) and oestrogen receptor-negative breast cancer cells (Biswas et al, 2001). This activation of NF-kB survival signalling is believed to provide a growth advantage in androgen-independent prostate cancer cells by suppressing apoptosis and inducing cell adhesion and angiogenic potential (Huang et al, 2001;Gasparian et al, 2002).…”

Section: Discussionmentioning

confidence: 71%

Quinazoline-based α1-adrenoceptor antagonists induce prostate cancer cell apoptosis via TGF-β signalling and IκBα induction

2003

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Previous studies documented the ability of quinazoline-based a1-adrenoceptor antagonists to induce apoptosis in prostate cancer cells via an a1-adrenoceptor-independent mechanism. In this study we investigated the molecular events initiating this apoptotic effect. Since transforming growth factor-b1 (TGF-b1) mediates prostate epithelial cell apoptosis, we hypothesised that the activation of the TGF-b1 pathway underlies the quinazoline-based apoptotic effect in prostate cancer cells. Treatment of the androgenindependent human prostate cancer cells PC-3 with doxazosin resulted in a strong caspase-3 activation within 24 h, whereas tamsulosin, a sulphonamide-based a1-adrenoceptor antagonist, had no significant apoptotic effect against prostate cancer cells. To identify the molecular components involved in this quinazoline-mediated apoptosis, cDNA microarray analysis of PC-3 prostate cancer cells treated with doxazosin (3 h) was performed. Induced expression of several genes was observed including p21 WAF-1 and IkBa (inhibitor of NF-kB alpha). Relative quantitative reverse transcription -polymerase chain reaction analysis revealed induction of several TGF-b1 signalling effectors: Induction of mRNA for Smad4 and the TGF-b1-regulated apoptosis-inducing transcription factor TGF-b1-inducible early gene (TIEG1) was detected within the first 6 h of doxazosin treatment. Upregulation of IkBa at both the mRNA and protein level was also detected after 6 h of treatment. Furthermore, doxazosin resulted in a considerable elevation in Smad4 and TIEG protein expression (6 h). A 'latent' increase in TGF-b mRNA expression was detected after 48 h of treatment. These findings suggest that the quinazoline-based doxazosin mediates prostate cancer apoptosis by initially inducing the expression of TGF-b1 signalling effectors and subsequently IkBa. The present study provides an initial insight into the molecular targets of the apoptotic action of quinazolines against prostate cancer cells.

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“…The possibility remains that maspin may sensitize induced apoptosis by inhibiting an intracellular protease. To this end, Biswas et al (2001) have shown that Go6976, an STS-derived compound that speci®cally inhibits PKC a-and b-subunits, induces the apoptosis of ER-negative breast carcinoma cells through the inhibition of NF-kB activity. Considering the evidence that NF-kB is primarily activated by the ubiquitin-mediated degradation of IkB, a cytosolic inhibitor of NF-kB in its p105 precursor (Lee and Goldberg, 1998;Palombella et al, 1994), it is intriguing to hypothesize that maspin may enhance STS-induced inactivation of NF-kB by blocking the proteolytic degradation of IkB.…”

Section: Discussionmentioning

confidence: 99%

Maspin sensitizes breast carcinoma cells to induced apoptosis

et al. 2002

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Maspin, a novel serine protease inhibitor (serpin), suppresses the growth and metastasis of breast tumor in vivo. However, the underlying molecular mechanism is unclear. In the current study, we report the ®rst evidence that endogenous maspin expression in mammary carcinoma cells MDA-MB-435 enhanced staurosporine (STS)-induced apoptosis as judged by the increased fragmentation of DNA, increased proteolytic inactivation of poly-[ADP-ribose]-polymerase (PARP), as well as the increased activation of caspase-8 and caspase-3. In parallel, recombinant maspin did not directly regulate the proteolytic activities of either caspase-3 or caspase-8 in vitro. Consistent with this result, maspin expressing normal mammary epithelial cells underwent more rapid STS-induced apoptosis as compared to breast carcinoma cells. Interestingly, maspin transfectant cells did not undergo spontaneous apoptosis in the absence of STS. Moreover, neither puri®ed maspin protein added from outside nor endogenous maspin secreted to the cell culture media sensitized cells to STS-induced apoptosis. To investigate the structural determinants of maspin in its apoptosis-sensitizing e ect, MDA-MB-435 cells were also transfected with maspin/PAI-1 and PAI-1/maspin chimeric constructs resulting from swapping the Nterminal and the C-terminal domains between maspin and PAI-1 (plasminogen activator inhibitor type 1). The resulting stable transfectant clones expressing maspin/ PAI-1 and PAI-1/maspin, respectively, did not undergo spontaneous apoptosis, and were similarly inhibited as maspin transfectant cells in motility assay. Interestingly, however, expression of both maspin/PAI-1 and PAI-1/ maspin in MDA-MB-435 cells failed to sensitize these cells to STS-induced apoptosis. Taken together, our evidence provides new insights into the complex molecular mechanisms of maspin that may suppress breast tumor progression not only at the step of invasion and motility, but also by regulating tumor cell apoptosis. The sensitizing e ect of maspin on apoptosis is to be contrasted by the pro-survival e ect of several other serpins.

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The nuclear factor kappa B (NF-κB): A potential therapeutic target for estrogen receptor negative breast cancers

Cited by 160 publications

References 38 publications

Distinct molecular phenotype of inflammatory breast cancer compared to non-inflammatory breast cancer using Affymetrix-based genome-wide gene-expression analysis

Distinct molecular phenotype of inflammatory breast cancer compared to non-inflammatory breast cancer using Affymetrix-based genome-wide gene-expression analysis

Quinazoline-based α1-adrenoceptor antagonists induce prostate cancer cell apoptosis via TGF-β signalling and IκBα induction

Maspin sensitizes breast carcinoma cells to induced apoptosis

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