Immunohistochemical Analysis of Prostate Apoptosis Response-4 (Par-4) in Mexican Women with Breast Cancer: A Preliminary Study

Méndez-López, Luis Fernando; Zapata‐Benavides, Pablo; Zavala-Pompa, Ángel; Aguado-Barrera, Miguel E.; Pacheco-Calleros, Javier; Rodríguez‐Padilla, Cristina; Cerda‐Flores, Ricardo M.; Cortés‐Gutiérrez, Elva I.; Dávila-Rodríguez, Martha I.

doi:10.1016/j.arcmed.2010.05.005

Cited by 16 publications

(13 citation statements)

References 33 publications

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“…Recently, down regulation of PAR-4 in transgenic mouse models of mammary tumorigenesis and in breast cancer patients was identified as an important mechanism of tumour cell survival and recurrence at both local and distant sites following chemotherapy and targeted therapy 21 . Low PAR-4 expression independently predicts decreased recurrence-free survival in women with breast cancer, which confirms the results from previous studies 17,18 . Importantly, PAR-4 expression was also found to be low in highly aggressive, estrogen-receptor negative (ER−), basal-like, and high-grade (grade 3) breast cancers, which are all associated with poor clinical outcome 21 .…”

Section: Introductionsupporting

confidence: 90%

PAR-4 overcomes chemo-resistance in breast cancer cells by antagonizing cIAP1

Guo

Treude

Krämer

et al. 2019

Sci Rep

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Most deaths from breast cancer result from tumour recurrence, which is typically an incurable disease. Down-regulation of the pro-apoptotic tumour suppressor protein prostate apoptosis response-4 (PAR-4) is required for breast cancer recurrence and resistance to chemotherapy. Recent advances in the analysis of apoptotic signalling networks have uncovered an important role for activation of caspase-8 following DNA damage by genotoxic drugs. DNA damage induces depletion of IAP proteins and causes caspase-8 activation by promoting the formation of a cytosolic cell death complex. We demonstrate that loss of PAR-4 in triple negative breast cancer cell lines (TNBC) mediates resistance to DNA damage-induced apoptosis and prevents activation of caspase-8. Moreover, loss of PAR-4 prevents DNA damage-induced cIAP1 depletion. PAR-4 functions downstream of caspase-8 by cleavage-induced nuclear translocation of the C-terminal part and we demonstrate that nuclear translocation of the C-terminal PAR-4 fragment leads to depletion of cIAP1 and subsequent caspase-8 activation. Specifically targeting cIAP1 with RNAi or Smac mimetics (LCL161) overcomes chemo-resistance induced by loss of PAR-4 and restores caspase-8 activation. Our data identify cIAP1 as important downstream mediator of PAR-4 and we provide evidence that combining Smac mimetics and genotoxic drugs creates vulnerability for synthetic lethality in TNBC cells lacking PAR-4.

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Section: Introductionsupporting

confidence: 90%

PAR-4 overcomes chemo-resistance in breast cancer cells by antagonizing cIAP1

Guo

Treude

Krämer

et al. 2019

Sci Rep

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show abstract

“…Through a series of well-designed experiments and adept analysis of human breast cancer datasets, the authors demonstrate that downregulation of Par-4 expression is an absolute prerequisite for tumor recurrence and conclude that low Par-4 expression is an independent predictor of decreased recurrence-free survival in women with breast cancer, which corroborates the findings from previous studies [8,9]. This is further exemplified by the finding that highly aggressive, estrogen receptor-negative, high-grade (grade 3), and basal-like tumors exhibit extremely low levels of Par-4.…”

Section: The Articlesupporting

confidence: 83%

Par-4 prevents breast cancer recurrence

Hebbar

Shrestha-Bhattarai

2013

Breast Cancer Res

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Therapy resistance and disease recurrence are two of the most challenging aspects in breast cancer treatment. A recent article in Cancer Cell makes a significant contribution toward a better understanding of this therapeutic problem by establishing downregulation of the tumor suppressor Par-4 as the primary determinant of breast cancer recurrence. This viewpoint brings forth the importance of their findings and its implications on future research and therapy.

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“…In light of our observation that Par-4 is frequently down-regulated during tumor recurrence in mice, and given the preliminary finding that low Par-4 expression is associated with poor prognosis in at least some breast cancer patients (Mendez-Lopez et al, 2010; Nagai et al, 2010), we asked whether low Par-4 expression is associated with an increased risk of recurrence in a broader panel of breast cancer patients. We obtained gene expression data from publicly availably human breast cancer datasets for which clinical outcome was available (Table S1) and examined the relationship between Par-4 expression and recurrence-free survival (RFS).…”

Section: Resultsmentioning

confidence: 99%

“…Low Par-4 expression has recently been shown to be associated with reduced overall survival in two patient cohorts, raising the possibility that Par-4 down-regulation may be associated with an increased risk of recurrence (Mendez-Lopez et al, 2010; Nagai et al, 2010). However, one of these studies examined only a small patient cohort (Mendez-Lopez et al, 2010), and the other found an association between Par-4 and overall survival, but not disease-free survival (Nagai et al, 2010). As such, the relationship between Par-4 down-regulation and breast cancer recurrence remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Par-4 Downregulation Promotes Breast Cancer Recurrence by Preventing Multinucleation following Targeted Therapy

et al. 2013

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Summary Most deaths from breast cancer result from tumor recurrence, but the mechanisms underlying tumor relapse are largely unknown. We now report that Par-4 is down-regulated during tumor recurrence and that Par-4 down-regulation is necessary and sufficient to promote recurrence. Tumor cells with low Par-4 expression survive therapy by evading a program of Par-4-dependent multinucleation and apoptosis that is otherwise engaged following treatment. Low Par-4 expression is associated with poor response to neoadjuvant chemotherapy and an increased risk of relapse in breast cancer patients, and Par-4 is down-regulated in residual tumor cells that survive neoadjuvant chemotherapy. Our findings identify Par-4-induced multinucleation as a mechanism of cell death in oncogene-addicted cells and establish Par-4 as a negative regulator of breast cancer recurrence.

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Immunohistochemical Analysis of Prostate Apoptosis Response-4 (Par-4) in Mexican Women with Breast Cancer: A Preliminary Study

Cited by 16 publications

References 33 publications

PAR-4 overcomes chemo-resistance in breast cancer cells by antagonizing cIAP1

PAR-4 overcomes chemo-resistance in breast cancer cells by antagonizing cIAP1

Par-4 prevents breast cancer recurrence

Par-4 Downregulation Promotes Breast Cancer Recurrence by Preventing Multinucleation following Targeted Therapy

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