The nuclear BAG-1 isoform, BAG-1L, enhances oestrogen-dependent transcription

Cutress, Ramsey I.; Townsend, Paul A.; Sharp, Adam; Maison, Anna; Wood, Lynn; Lee, Ron; Brimmell, Matthew; Mullee, Mark; Johnson, Peter; Royle, G. T.; Bateman, A C; Packham, Graham

doi:10.1038/sj.onc.1206688

Cited by 69 publications

(111 citation statements)

References 49 publications

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“…Although these experiments were primarily focused on the role of BAG-1 in the development of the malignant process in the breast, it is nonetheless of interest to speculate how they may relate to the association between high BAG-1 expression and improved outcome for breast cancer patients observed by us and others (Turner et al, 2001;Cutress et al, 2003;Millar et al, 2008;Nadler et al, 2008). One possible explanation for this apparent dichotomy lies in the inherent heterogeneity in BAG-1's actions, such that its pro-survival effects may have an important role during tumor initiation, but lead to the formation of a less aggressive or more therapeutically responsive cancer, for example, through its known effects on nuclear hormone receptor function.…”

Section: Discussionmentioning

confidence: 99%

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BAG-1 overexpression attenuates luminal apoptosis in MCF-10A mammary epithelial cells through enhanced RAF-1 activation

2009

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Although the multi-functional, prosurvival protein, Bcl-2-associated anthanogene 1 (BAG-1) is frequently overexpressed in breast cancers, its role in the development or maintenance of the malignant state remains unclear. Here, we have used the established MCF-10A 3-dimensional (3D) model of mammary morphogenesis as a biologically relevant system to determine how BAG-1 expression may influence the development of breast cancer. When cultured in 3D, MCF-10A cells undergo a highly regulated morphogenic program leading to the development of polarized acinar structures containing a central, hollow lumen formed, in part, through the induction of BIM-dependent apoptosis. BAG-1 overexpression resulted in an attenuation of this normal apoptotic program characterized by a significantly increased number of acini with filled lumens-a phenotype commonly observed in ductal carcinoma in situ. BAG-1's effects were associated with an activation of RAF-1-a known binding partner of BAG-1, enhanced signaling through the MAP kinase pathway and a decrease in BIM expression. Reversal of the BAG-1-associated survival phenotype by the mitogen-activated kinase/ERK kinase inhibitor, U0126, implicates the RAF-1-extracellular signal-regulated kinase signaling pathway as a major mediator of BAG-1's effects in this model. As BAG-1 expression is often elevated in preinvasive breast cancers, these findings support a possible role for BAG-1 as an early contributor to the malignant process in the breast.

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Section: Discussionmentioning

confidence: 99%

“…This differential localization may also dictate functional differences between the isoforms. For example, only BAG-1L interacts with the nuclear hormone receptors, estrogen receptor (ER) and androgen receptor leading to an enhancement in their transcriptional activity (Froesch et al, 1998;Cutress et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

BAG-1 overexpression attenuates luminal apoptosis in MCF-10A mammary epithelial cells through enhanced RAF-1 activation

2009

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“…In this study, elevated cytoplasmic BAG-1 expression was associated with improved prognosis in a multivariate model that included ER, BCL-2 and stage. In a more homogeneous and representative cohort of early breast cancer, Cutress et al (2003) described improved prognosis in univariate analysis with high nuclear, but not high cytoplasmic, BAG-1 expression in a cohort of 138 patients, 60% of whom were ER þ . All patients were treated with surgery and endocrine therapy without chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have attempted to relate BAG-1 protein expression to disease outcome with inconsistent results, which may have been the result of low patient numbers, low rates of ER þ tumours (ER þ rates of 35 -52% rather than a currently expected rate of B70%) and incomplete pathological, clinical and treatment information. However, the improved prognosis associated with a high BAG-1 expression has earlier been demonstrated in three studies although with differences in subcellular localisation of BAG-1 expression that is, cytoplasmic (Turner et al, 2001), nuclear (Cutress et al, 2003), and cytoplasmic or nuclear (Nadler et al, 2008). More recently, BAG-1 featured as one of the 16 cancerspecific genes included in the Oncotype Dx assay (Paik et al, 2004), which predicts distant failure in ER þ , lymph node-negative patients treated with tamoxifen using PCR of formalin-fixed paraffin-embedded (FFPE) material.…”

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confidence: 99%

“…BAG-1 exists as three protein isoforms. The specific ability of the long isoform, BAG-1L (p50), which possesses a nuclear localisation sequence not present in the other isoforms, to upregulate the transcriptional activity of both ERa and ERb up to five-fold in MCF-7 breast cancer cells (Cutress et al, 2003), is of potential functional and prognostic significance. BAG-1 is expressed in most normal human tissues , and its overexpression has been described not only in breast cancer, but also in other human malignancies including squamous cell carcinoma of the head and neck (Shindoh et al, 2000), chronic lymphocytic leukaemia and prostate cancer (Maki et al, 2007), in which it is associated with a poor prognosis.…”

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confidence: 99%

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BAG-1 predicts patient outcome and tamoxifen responsiveness in ER-positive invasive ductal carcinoma of the breast

et al. 2008

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BAG-1 (bcl-2-associated athanogene) enhances oestrogen receptor (ER) function and may influence outcome and response to endocrine therapy in breast cancer. We determined relationships between BAG-1 expression, molecular phenotype, response to tamoxifen therapy and outcome in a cohort of breast cancer patients and its influence on tamoxifen sensitivity in MCF-7 breast cancer cells in vitro . Publically available gene expression data sets were analysed to identify relationships between BAG-1 mRNA expression and patient outcome. BAG-1 protein expression was assessed using immunohistochemistry in 292 patients with invasive ductal carcinoma and correlated with clinicopathological variables, therapeutic response and disease outcome. BAG-1-overexpressing MCF-7 cells were treated with antioestrogens to assess its effects on cell proliferation. Gene expression data demonstrated a consistent association between high BAG-1 mRNA and improved survival. In ER+ cancer ( n =189), a high nuclear BAG-1 expression independently predicted improved outcome for local recurrence ( P =0.0464), distant metastases ( P =0.0435), death from breast cancer ( P =0.009, hazards ratio 0.29, 95% CI: 0.114–0.735) and improved outcome in tamoxifen-treated patients ( n =107; P =0.0191). BAG-1 overexpression in MCF-7 cells augmented antioestrogen-induced growth arrest. A high BAG-1 expression predicts improved patient outcome in ER+ breast carcinoma. This may reflect both a better definition of the hormone-responsive phenotype and a concurrent increased sensitivity to tamoxifen.

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Bag‐1‐mediated HSF1 phosphorylation regulates expression of heat shock proteins in breast cancer cells

Kizilboga,

Özden,

Can

et al. 2024

FEBS Open Bio

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According to the World Health Organization in 2022, 2.3 million women were diagnosed with breast cancer. Investigating the interaction networks between Bcl‐2‐associated athanogene (Bag)‐1 and other chaperone proteins may further the current understanding of the regulation of protein homeostasis in breast cancer cells and contribute to the development of treatment options. The present study aimed to determine the interactions between Bag‐1 and heat shock proteins (HSPs); namely, HSP90, HSP70 and HSP27, to elucidate their role in promoting heat shock factor‐1 (HSF1)‐dependent survival of breast cancer cells. HER2‐negative (MCF‐7) and HER2‐positive (BT‐474) cell lines were used to examine the impact of Bag‐1 expression on HSF1 and HSPs. We demonstrated that Bag‐1 overexpression promoted HER2 expression in breast cancer cells, thereby resulting in the concurrent constitutive activation of the HSF1–HSP axis. The activation of HSP results in the stabilization of several tumor‐promoting HSP clients such as AKT, mTOR and HSF1 itself, which substantially accelerates tumor development. Our results suggest that Bag‐1 can modulate the chaperone activity of HSPs, such as HSP27, by directly or indirectly regulating the phosphorylation of HSF1. This modulation of chaperone activity can influence the activation of genes involved in cellular homeostasis, thereby protecting cells against stress.

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The nuclear BAG-1 isoform, BAG-1L, enhances oestrogen-dependent transcription

Cited by 69 publications

References 49 publications

BAG-1 overexpression attenuates luminal apoptosis in MCF-10A mammary epithelial cells through enhanced RAF-1 activation

BAG-1 overexpression attenuates luminal apoptosis in MCF-10A mammary epithelial cells through enhanced RAF-1 activation

BAG-1 predicts patient outcome and tamoxifen responsiveness in ER-positive invasive ductal carcinoma of the breast

Bag‐1‐mediated HSF1 phosphorylation regulates expression of heat shock proteins in breast cancer cells

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