Bax immunohistochemical expression in breast carcinoma: A study with long term follow-up

Veronese, Silvio; Mauri, Francesco; Caffo, Orazio; Scaioli, Monica; Aldovini, D; Perrone, Giorgio; Galligioni, Enzo; Doglioni, Claudio; Palma, Paolo Dalla; Barbareschi, Mattia

doi:10.1002/(sici)1097-0215(19980220)79:1<13::aid-ijc3>3.0.co;2-z

Cited by 48 publications

(50 citation statements)

References 17 publications

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“…Many authors have simply recorded the presence of various markers of apoptosis and have assumed either explicitly or implicitly that there is a cause and effect relationship between their expression and loss of cell viability. Other studies have correlated the expression of pro-or anti-apoptotic genes in a variety of human cancers with their overall responsiveness to therapy: some have found a positive relationship (Kramer et al, 1996;Tai et al, 1998) whereas others have not (Pereira et al, 1997;Veronese et al, 1998). Even in studies which show a positive correlation, a cause and effect relationship has not been established.…”

Section: Discussionmentioning

confidence: 99%

Evidence against apoptosis as a major mechanism for reproductive cell death following treatment of cell lines with anti-cancer drugs

Tannock

Lee

2001

Br J Cancer

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An increase in apoptotic cells may be observed after treatment with chemotherapy, and many authors have assumed that anti-cancer drugs kill cells by inducing apoptosis. The most relevant endpoint of cell death following treatment of tumour cells is loss of reproductive ability as measured by a colony-forming assay, since cells with limited reproductive potential cannot regenerate a tumour. We have therefore investigated the relationship between apoptosis and reproductive cell death following in vitro treatment of mammalian cell lines with anti-cancer drugs. Markers of apoptosis (DNA ladders, TUNEL assay) were evaluated at various times after treatment of Chinese Hamster Ovary (CHO) cells, human bladder cancer MGH-U1 cells, and a murine T-lymphocytic cell line (CTLL-2) with several anti-cancer drugs. These markers were found infrequently, despite the use of doses that cause loss of colony-forming ability, except in CTLL-2 cells. We also transfected and expressed the human pro-apoptotic gene bax and the anti-apoptotic gene bcl-2 in MGH-U1 cells and compared cell survival after drug treatment with that of control cells transfected with the vector alone. Expression of these genes had at most small effects to influence cell survival. We conclude that apoptotic mechanisms had at most a minor role in leading to reproductive death of MGH-U1 and CHO cells after chemotherapy. When apoptosis is observed following treatment with anti-cancer drugs it may be a secondary event which occurs in lethally-damaged cells, leading to their lysis, rather than a primary event that leads to loss of reproductive integrity. © 2001 Cancer Research Campaign http://www.bjcancer.com

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Section: Discussionmentioning

confidence: 99%

Evidence against apoptosis as a major mechanism for reproductive cell death following treatment of cell lines with anti-cancer drugs

Tannock

Lee

2001

Br J Cancer

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“…Previous to this study, it had been shown that wild-type p53 can bind directly to the Bax gene promoter and induce its transcriptional activation, at least in some types of permissive cells (Miyashita & Reed 1995). However, in breast cancers, no correlation between the percentages of Bax-and p53-immunopositive tumor cells was observed when examined as either dichotomous or continuous variables (Veronese et al 1998).…”

Section: Bax As a Tumor Suppressor Genementioning

confidence: 94%

Prognostic significance of apoptosis regulators in breast cancer.

Krajewski¹,

Krajewska²,

Turner³

et al. 1999

Endocrine-Related Cancer

166

100

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Dysregulation of normal programmed cell death mechanisms plays an important role in the pathogenesis and progression of breast cancer, as well as in responses of tumors to therapeutic intervention. Overexpression of anti-apoptotic members of the Bcl-2 family such as Bcl-2 and Bcl-X(L) has been implicated in cancer chemoresistance, whereas high levels of pro-apoptotic proteins such as Bax promote apoptosis and sensitize tumor cells to various anticancer therapies. Though the mechanisms by which Bcl-2 family proteins regulate apoptosis are diverse, ultimately they govern decision steps that determine whether certain caspase family cell death proteases remain quiescent or become active. To date, approximately 17 cellular homologs of Bcl-2 and at least 15 caspases have been identified in mammals. Other types of proteins may also modulate apoptotic responses through effects on apoptosis-regulatory proteins, such as BAG-1-a heat shock protein 70 kDa (Hsp70/Hsc70)-binding protein that can modulate stress responses and alter the functions of a variety of proteins involved in cell death and division. In this report, we summarize our attempts thus far to explore the expression of several Bcl-2 family proteins, caspase-3, and BAG-1 in primary breast cancer specimens and breast cancer cell lines. Moreover, we describe some of our preliminary observations concerning the prognostic significance of these apoptosis regulatory proteins in breast cancer patients, contrasting results derived from women with localized disease (with or without node involvement) and metastatic cancer.

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“…In all but two of the published studies on a total of over 1200 patients (Table 2), mostly on patients with stage I tumors subjected only to local-regional treatment until relapse (Joensuu et al 1994, Silvestrini et al 1994, Hellemans et al 1995, Lipponen et al 1995, Barbareschi et al 1996, Van Slooten et al 1996, Kapranos et al 1997, Krajewski et al 1997, Charpin et al 1998, Veronese et al 1998), a general advantage in terms of relapse-free and overall survival was reported for patients with Bcl-2-overexpressing tumors. However, such an advantage was generally lost in multivariate analyses including information provided by tumor size, morphologic features, grade, proliferative rate, p53 expression and steroid receptors (Silvestrini et al 1994, Hellemans et al 1995, Lipponen et al 1995, Charpin et al 1998 or at a longer follow-up (Joensuu et al 1994).…”

Section: Relationship Between Bcl-2 Expression and Prognosismentioning

confidence: 99%

“…Since the therapeutic effect of hormones may be mediated by activation of the apoptotic program, its suppression or delay by Bcl-2 might result in treatment failure. However, as regards such a hypothesis, in almost all the published reports dealing with a total of over 1000 patients (Table 3), the expression of Bcl-2 surprisingly appears as an indicator of a favorable outcome following endocrine treatment in patients with limited disease (Gasparini et al 1995, Hurlimann et al 1995, Silvestrini et al 1996, Hellemans et al 1995, Kobayashi et al 1997, Veronese et al 1998 and as a predictor of treatment response in patients with advanced disease (Gee et al 1994, Elledge et al 1997, Keen et al 1997. In addition, within ERpositive tumors, the integration of clinically relevant information provided by biologic variables that proved to be independent in multivariate analysis (cell proliferation, progesterone receptors (PgR), p53 and Bcl-2 expression) allowed us to separate patients with ER-positive tumors into different risk groups.…”

Section: Relationship Between Bcl-2 Expression and Response To Endocrmentioning

confidence: 99%

“…However, in retrospective studies on clinical breast cancer subjected to different treatment regimens (cyclophosphamide and 5-fluorouracil, plus methotrexate (CMF) or epidoxorubicin (FEC), or doxorubicin alone) (Table 4), Bcl-2 expression did not appear to provide information on objective clinical response in terms of tumor reduction (Krajewski et al 1995, Frassoldati et al 1997, Collecchi et al 1998, Ellis et al 1998, whereas a favorable outcome in terms of relapse-free or overall survival was generally observed for patients with Bcl-2-positive tumors (Gasparini et al 1995, Krajewski et al 1995, Lipponen et al 1995, Veronese et al 1998. In the only randomized trial reported in the literature in which Bcl-2 expression was determined (Van Slooten et al 1996), comparing perioperative 5-fluorouracil, doxorubicin and cyclophosphamide (FAC) with surgery alone, a treatment benefit was observed for Bcl-2-positive but also for Bcl-2-negative tumors.…”

Section: Relationship Between Bcl-2 Expression and Response To Chemotmentioning

confidence: 99%

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Clinical studies of Bcl-2 and treatment benefit in breast cancer patients.

Daidone¹,

Luisi²,

Veneroni³

et al. 1999

Endocrine-Related Cancer

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Interest in translational studies aimed at investigating the role of biologic markers in predicting clinical outcome of breast cancer patients and, in particular, response to specific treatments, has progressively increased. Among biologic variables presently under investigation, apoptosis markers, in particular Bcl-2 and Bax expression, are receiving much attention for their relationship with the cellular response to genotoxic damage in experimental tumors. Retrospective, independent studies were carried out by several research groups on about 5000 patients with breast cancer at different stages and with an adequate follow-up. The outcome of separate analyses as a function of treatment generally demonstrated that Bcl-2 overexpression, which correlates with biologic features of a differentiated phenotype (slow proliferation, high steroid receptor levels, absence of p53 and c-erB-2 expression), is associated with a favorable outcome. Such a finding is mainly evident following surgery as well as endocrine treatment. Conversely, no or weak Bcl-2 expression, alone or in association with bax overexpression, appears indicative of a radiation response, and preliminary emerging evidence supports the involvement of such an association of apoptosis-related markers even as predictors of long-term response to neoadjuvant cytotoxic treatment. Although the findings of an involvement of Bcl-2 and Bax as determinants of treatment response should be confirmed within the context of randomized clinical trials, they indicate a combined consideration of proteins that negatively and positively regulate apoptosis in translational studies on the effect of chemical and physical agents at a cellular level.

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Bax immunohistochemical expression in breast carcinoma: A study with long term follow-up

Cited by 48 publications

References 17 publications

Evidence against apoptosis as a major mechanism for reproductive cell death following treatment of cell lines with anti-cancer drugs

Evidence against apoptosis as a major mechanism for reproductive cell death following treatment of cell lines with anti-cancer drugs

Prognostic significance of apoptosis regulators in breast cancer.

Clinical studies of Bcl-2 and treatment benefit in breast cancer patients.

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