Identification of PUMA as an estrogen target gene that mediates the apoptotic response to tamoxifen in human breast cancer cells and predicts patient outcome and tamoxifen responsiveness in breast cancer

Roberts, Caroline G.P.; Millar, Ewan K.A.; O’Toole, Sandra A.; McNeil, Catriona M.; Lehrbach, Gillian M.; Pinese, Mark; Tobelmann, Page E; McCloy, Rachael A.; Musgrove, Elizabeth A.; Sutherland, Robert L.; Butt, Alison J.

doi:10.1038/onc.2011.36

Cited by 21 publications

(25 citation statements)

References 36 publications

(49 reference statements)

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“…The direction of change of BBC3 mRNA levels is entirely consistent with the effects of FGF18 and estradiol on caspase-3 activation and the incidence of apoptosis. An inhibitory effect of estradiol on BBC3 expression has also been observed in breast cancer cells and the ischemic hippocampus [43,44].…”

Section: Discussionmentioning

confidence: 94%

The Role of Fibroblast Growth Factor-18 in Follicular Atresia in Cattle1

Portela

Dirandeh

Guerrero-Netro

et al. 2015

Biology of Reproduction

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Although the various members of the fibroblast growth factor (FGF) family are generally mitotic, one member, FGF18, has been shown to increase the rate of apoptosis of ovarian granulosa cells. In the present study, we first determined whether granulosa cells express FGF18 and we then explored the mechanism through which FGF18 increases apoptosis in vitro. Under culture conditions that favored estradiol secretion and CYP19A1 expression, granulosa FGF18 mRNA levels were barely detectable; however, withdrawing gonadotropic support (follicle-stimulating hormone or insulin-like growth factor 1) reduced levels of CYP19A1 mRNA and increased abundance of mRNA encoding the death ligand FASLG and FGF18. Addition of FGF18, but not FGF2, FGF10, or EGF, increased the proportion of apoptotic cells and frequency of caspase 3 activation, and these effects were abrogated by coculture with estradiol. Addition of FGF18 decreased abundance of mRNA encoding the antiapoptotic proteins GADD45B and MDM2, and increased that encoding the proapoptotic protein BBC3; these effects were reversed by coculture with estradiol. The physiological relevance of FGF18 was determined using an in vivo model: injection of FGF18 directly into growing bovine dominant follicles caused cessation of follicle growth by 24 h after injection. Collectively, these data demonstrate that FGF18 is proapoptotic in vivo and may act through a mechanism involving the BBC3-MDM2 pathway.

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Section: Discussionmentioning

confidence: 94%

The Role of Fibroblast Growth Factor-18 in Follicular Atresia in Cattle1

Portela

Dirandeh

Guerrero-Netro

et al. 2015

Biology of Reproduction

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“…Additional in vivo experiments will be necessary to determine whether targeting ERBB receptors could restore tamoxifen response or increase the antitumor activity of fulvestrant in the HBCx34 TamR xenograft. A number of genes involved in cell growth, cell death, and cell-cycle control were modulated in hormono resistant tumors; these biologic functions have been frequently associated with endocrine resistance both in vitro and in vivo (2,48,49). In patients, cell cycle, cell growth, and cell survival signatures are independent predictors of outcome in tamoxifen-treated patients (50).…”

Section: Discussionmentioning

confidence: 99%

Acquired Resistance to Endocrine Treatments Is Associated with Tumor-Specific Molecular Changes in Patient-Derived Luminal Breast Cancer Xenografts

Cottu¹,

Bièche

Assayag³

et al. 2014

Clinical Cancer Research

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Purpose: Patients with luminal breast cancer (LBC) often become endocrine resistant over time. We investigated the molecular changes associated with acquired hormonoresistances in patient-derived xenografts of LBC. Experimental Design: Two LBC xenografts (HBCx22 and HBCx34) were treated with different endocrine treatments (ET) to obtain xenografts with acquired resistances to tamoxifen (TamR) and ovariectomy (OvaR). PI3K pathway activation was analyzed by Western blot analysis and IHC and responses to ET combined to everolimus were investigated in vivo. Gene expression analyses were performed by RT-PCR and Affymetrix arrays. Results: HBCx22 TamR xenograft was cross-resistant to several hormonotherapies, whereas HBCx22 OvaR and HBCx34 TamR exhibited a treatment-specific resistance profile. PI3K pathway was similarly activated in parental and resistant xenografts but the addition of everolimus did not restore the response to tamoxifen in TamR xenografts. In contrast, the combination of fulvestrant and everolimus induced tumor regression in vivo in HBCx34 TamR, where we found a cross-talk between the estrogen receptor (ER) and PI3K pathways. Expression of several ER-controlled genes and ER coregulators was significantly changed in both TamR and OvaR tumors, indicating impaired ER transcriptional activity. Expression changes associated with hormonoresistance were both tumor and treatment specific and were enriched for genes involved in cell growth, cell death, and cell survival. Conclusions: PDX models of LBC with acquired resistance to endocrine therapies show a great diversity of resistance phenotype, associated with specific deregulations of ER-mediated gene transcription. These models offer a tool for developing anticancer therapies and to investigate the dynamics of resistance emerging during pharmacologic interventions. Clin Cancer Res; 20(16); 4314–25. ©2014 AACR.

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“…Preclinical models suggest that the use of anti-vascular endothelial growth factor (anti-VEGF) therapy with antiestrogens may prevent or delay the development of endocrine therapy resistance [51]. A feasibility study of letrozole and bevacizumab in combination has been reported, and phase III trials of endocrine therapy plus bevacizumab are in progress [52].…”

Section: Role Of Angiogenesis In Hormonal Resistancementioning

confidence: 99%

“…The BCL-2 homology 3, pro-apoptotic regulator, PUMA (p53 upregulated modulator of apoptosis) has been studied as an estrogen target gene that is acutely downregulated in response to estrogen in breast cancer cell lines, independently of the p53 tumor suppressor status. PUMA has been found to be transcriptionally upregulated following treatment with tamoxifen, and low PUMA expression in breast carcinomas is significantly associated with breast cancer mortality and poor outcome [52].…”

Section: Other Pathwaysmentioning

confidence: 99%

Hormonal Resistance in Breast Cancer: Evolving Treatment Strategies

Khasraw¹,

Harvey

2012

Curr Breast Cancer Rep

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About 70% of breast cancers are hormone receptor (HR) positive, meaning an estrogen receptor (ER) and/or a progesterone receptor (PgR) are present in the tumor. Compounds that modulate ER or PgR signaling, by either competing for estrogen binding to estrogen receptors (synthetic estrogen receptor modulators [eg, tamoxifen]) or opposing the production of estrogen in the body (aromatase inhibitors in postmenopausal women), are dominant among those used to treat HR-positive breast cancer. Although HRpositive tumors are associated with a better prognosis, in the case of advanced disease, most will develop resistance to hormonal treatments over time. Multiple mechanisms of endocrine resistance have been proposed, including ER receptor loss and cross-talk between the ER and HER2/neu (human epidermal growth factor receptor 2; also known as ErbB-2) receptor signaling pathways. The phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homologue deleted on chromosome ten (PTEN)/Akt/mammalian target of rapamycin (mTOR) pathway is often implicated in sensitivity and resistance to therapy. Dysregulated signaling through the PI3K/PTEN/Akt/mTOR pathway may result from genetic alterations in critical components in this pathway. Therapeutic targeting of alternate pathways of growth signaling in ER-positive tumors has the potential to translate into practice-changing therapeutic strategies. This article discusses the concept of primary and secondary endocrine resistance, outlines the proposed mechanisms, and reviews the emerging evidence for interventions designed to overcome resistance and restore ER sensitivity. The recently reported result of the BOLERO-2 study using an mTOR inhibitor (everolimus or RAD001) in combination with an aromatase inhibitor (exemestane) is discussed in some detail.

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Identification of PUMA as an estrogen target gene that mediates the apoptotic response to tamoxifen in human breast cancer cells and predicts patient outcome and tamoxifen responsiveness in breast cancer

Cited by 21 publications

References 36 publications

The Role of Fibroblast Growth Factor-18 in Follicular Atresia in Cattle1

The Role of Fibroblast Growth Factor-18 in Follicular Atresia in Cattle1

Acquired Resistance to Endocrine Treatments Is Associated with Tumor-Specific Molecular Changes in Patient-Derived Luminal Breast Cancer Xenografts

Hormonal Resistance in Breast Cancer: Evolving Treatment Strategies

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