Bcl-2 with loss of apoptosis allows accumulation of genetic alterations: A pathway to metastatic progression in human breast cancer

Sierra, Àngels; Castellsagué, Xavier; Escobedo, A.; Lloveras, Belén; Garcia-Ramírez, Marta; Moreno, Abelardo; Fabra, Àngels

doi:10.1002/(sici)1097-0215(20000320)89:2<142::aid-ijc7>3.0.co;2-b

Cited by 39 publications

(21 citation statements)

References 15 publications

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“…Interestingly, Bcl-2 overexpressing clones from the human breast cancer cell line MCF7 ADR injected into nude mice induce a significantly higher number of lung metastases compared to the control transfectant clone, suggesting that bcl-2 overexpression may increase the invasive capacity of breast cancer cells (Del Bufalo et al, 1997). Consistent with this, Bcl-2 expression has been strongly associated with both apoptosis loss and presence of lymph node metastases in tumor samples from patients with ductal breast carcinomas (Sierra et al, 1996), which indicates that inhibition of apoptosis might facilitate the acquisition of additional genetic alterations associated to disease progression . Other Bcl-2 family members have also been associated with breast cancer.…”

Section: Introductionmentioning

confidence: 66%

Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells

et al. 2002

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Disruption of apoptosis may allow metastatic cell survival and confer resistance to chemotherapeutic drugs. We have analysed the molecular pathways that activate these survival genes in specific sites of metastasis. Estrogen receptor-negative breast cancer cell line MDA-MB435 and two metastatic sublines derived from lung (435L) and brain (435B) were analysed for the expression of members of the Bcl-2 family of apoptosis regulators. The levels of Bcl-2 were higher in the metastatic sublines than in parental cells, which correlated with the activation of Stat3, but not with the expression and/or activation of known bcl-2 transcription factors (CREB and WT1). In the brain subline, both expression of Bcl-2 and Stat3 activation were induced by epidermal growth factor and abrogated after treatment with kinase inhibitors specific for epidermal growth factor receptor or Jak2. Furthermore, transfection of 435B with a dominant-negative Stat3 markedly reduced the expression of Bcl-2 protein, whereas transient expression of a constitutively active Stat3 increased Bcl-2 in parental 435 cells. In addition, blockade of Stat3 activation by treatment with epidermal growth factor receptor and Jak2 kinase inhibitors or transfection with a dominant negative Stat3, sensitizes 435B cells to chemotherapy-induced apoptosis. Our data suggest that an increased activation of the Stat3 -Bcl-2 pathway in estrogen receptor-negative metastatic breast cancer cell lines confer a survival advantage to these cells and contribute to their chemoresistance.

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Section: Introductionmentioning

confidence: 66%

Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells

et al. 2002

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“…Recently, we identified loss of apoptosis and Bcl-2 overexpression in T 1 ductal breast carcinomas and this phenotype was associated with the likelihood of lymph node metastasis in patients, 15 and with accumulated oncogene alterations. 16 We have also reported Bcl-x L overexpression in these carcinomas, but Bcl-x L and Bcl-2 in human breast cancer may not be functionally redundant because expression of Bcl-x L is higher in HGIII than in HGI or HGII, in which Bcl-2 is predominant. 14 Importantly, those genes might be The aim of this work was to explore the role of Bcl-x L in the metastatic progression of breast cancer.…”

Section: Introductionmentioning

confidence: 81%

Bcl-xL promotes metastasis of breast cancer cells by induction of cytokines resistance

et al. 2000

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Metastasis is a highly complex process involving the survival of tumor cells, both in the blood stream and within specific organs. Cell-death and survival are determined by a number of gene products from an expanding family of the Bcl-2 gene, either promoting or preventing apoptosis. Furthermore, the survival of tumor cells may favor the accumulation of additional genetic alterations causing further growth and invasive opportunities which may lead to metastasis. To examine whether the prevention of cell-death influences the metastatic behavior, we transfected a human breast cancer cell line MDA-MB-435 with the Bcl-x L cDNA and then studied metastatic ability of the selected clones in vivo. Our results show that Bcl-x L -clones had a decreased tumor growth latency and an increased metastatic ability. Apoptosisresistance to cytokines was induced in 435 cells by Bcl-x Lexpression with minor modifications in their proliferation rates. These cells also showed diminished adhesion to extracellular matrix proteins and a survival advantage in suspension over 435/Neo cells. Moreover, to determine survival in blood stream and in cells lodged in the lungs, we injected 435/Bcl-x L and 435/Neo cells at 1 : 3 proportion i.v., and animals were killed at intervals of 15' to 16 h after injection. Tumor cells were recovered from the lungs and Southern-blot analysis revealed the presence of exogenous Bcl-x L cDNA. These results showed that 435/Bcl-x L cells had a survival advantage in circulation over 435/Neo cells. This advantage in vivo was attributable to Bcl-x L expression. We conclude that Bcl-x L expression in breast cancer cells can increase metastatic activity. This advantage could be created by inducing resistance to apoptosis against cytokines, increasing cell survival in circulation, and enhancing anchorageindependent growth.Cell Death and Differentiation (2000) 7, 350 ± 359.

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“…The amplification of the chromosomal region that contains the c-myc gene has also been reported to contain, apparently through translocation events, the p40 subunit of eukaryotic translation initiation factor 3 (eIF3) and the Her2 gene (Nupponen et al 1999), although the frequency of co-localization of these two genes in a common amplicon has not been established (Deming et al 2000). Her2 (also termed erbb2) is a gene in Locker et al (1989) IHC Not related to any clinicopathologic parameters Machotka et al (1989) SB More frequently in patients with node metastases Spandidos et al (1989a) ELISA Not correlated with survival Spandidos et al (1989b) IHC Not correlated with node metastasis Tauchi et al (1989) IHC Not correlated with ER, tumor histology or sizes Tavassoli et al (1989) SB,Slot-B Correlated with tumour grade, but not with metastasis Tsuda et al (1989) Slot-B Correlated with poor prognosis Walker et al (1989) ISH Spaventi et al (1994) IHC Not related to clinicopathologic parameters Pechoux et al (1994) SB,ISHS,IHC Also overexpressed in benign lesions Soini et al (1994) SB Mimori et al (1998) RT-PCR Correlated with ODC expression Stanta et al (1998) RT-PCR No clinicopathologic parameters mentioned Bieche et al (1999) RT-PCR Correlated with tumor size but inversely with survival Le et al (1999) NB Related to positive nodes Nupponen et al (1999) SSH Associated with eIF 3-amplification Schraml et al (1999) FISH Amplification detected in tissue-microarray Scorilas et al (1999) SB,NB Related to survival and local recurrence Sierra et al (1999) IHC Related to metastasis when Bcl-2 also increased Vos et al (1999) SB , WB Not related to Beta-catenin Rao et al (2000) PCR Up to 94% biopsies with amplification Sierra et al (2000) IHC Not related to clinicopathologic parameters CGH, comparative genomic hybridization; Dot-B, dot blot; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; ISH, in situ hybridization; NB, northern blot; RT-PCR, reverse transcription and PCR; SB, southern blot; Slot-B, slot blot; SSCP, single-strand conformation polymorphism; SSH, suppression substractive hybridization; WB; western blot; IGF1R, insulin-like growth factor-1; DCIS, ductal carcinoma in situ.…”

Section: The C-myc Gene In Human Breast Cancermentioning

confidence: 99%

c-Myc in breast cancer.

Liao¹,

Dickson²

2000

Endocrine-Related Cancer

316

265

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Ever since Bishop and his co-workers discovered the c-myc gene in the late 1970s (Bishop 1982), voluminous literature has documented its central role in proliferation and malignant transformation of human and animal cells (Amati et al. 1998, Bouchard et al. 1998, Dang et al. 1999). Most, if not all, types of human malignancy have been reported to have amplification and/or overexpression of this gene, although the frequency of these alterations varies greatly among different reports (Nesbit et al. 1999). In 1992, researchers started to realize that aberrant expression of c-myc could cause apoptosis (Evan et al. 1992, Shi et al. 1992), although the phenomenon had actually been observed much earlier (Wurm et al. 1986). Studies in recent years have further shown that the c-myc gene regulates growth, both in the sense of cell size and in the context of tissue differentiation (Gandarillas & Watt 1997, Iritani & Eisenman 1999, Johnston et al. 1999, Schmidt 1999, Schuhmacher et al. 1999). Thus, it is now known that the c-myc gene participates in most aspects of cellular function, including replication, growth, metabolism, differentiation, and apoptosis (Packham & Cleveland 1995, Hoffman & Liebermann 1998, Dang 1999, Dang et al. 1999, Elend & Eilers 1999, Prendergast 1999). How the c-Myc protein may be specifically directed to perform one, but not the others, of these functions is still obscure, despite the fact that the relevant literature has been accumulating at a fast pace in the past two decades. This review focuses on the profound roles of c-Myc in breast cancer and in the actions of the hormones that are eitologically related to breast cancer.

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Bcl-2 with loss of apoptosis allows accumulation of genetic alterations: A pathway to metastatic progression in human breast cancer

Cited by 39 publications

References 15 publications

Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells

Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells

Bcl-xL promotes metastasis of breast cancer cells by induction of cytokines resistance

c-Myc in breast cancer.

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