Growth factor-driven mechanisms associated with resistance to estrogen deprivation in breast cancer: new opportunities for therapy

Nicholson, Robert Ian; Staka, Cindy M.; Boyns, Frances Elizabeth; Hutcheson, Iain Robert; Gee, Julia Margaret Wendy

doi:10.1677/erc.1.00778

Cited by 86 publications

(81 citation statements)

References 107 publications

(76 reference statements)

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“…Moreover, promotion of ER negativity appears achievable in vitro when hormone-responsive cells are subject to sustained EGFR signalling during very prolonged ER blockade. This is exemplified by our MCF-7 model that, after extended culture with the pure antioestrogen faslodex, gains EGFR signalling but completely lacks ER, a feature irreversible on antioestrogen withdrawal (Nicholson et al 2004c). Further supportive evidence can be drawn from transfection studies where constitutively active components of EGFR/HER2 signalling introduced into ER + MCF-7 cells (notably MEK1…”

Section: Introductionmentioning

confidence: 74%

“…However, our group has demonstrated that complete dislocation from ER is also possible when growth factor signalling is substantially elevated. Exposure of MCF-7 cells to the ERBB ligand heregulin, which markedly upregulates MAPK and AKT signalling, is associated with lack of response to all endocrine manipulation (Nicholson et al 2004c). Similarly, secondline response to faslodex in our acquired TAMR cells can be abrogated by further hyperactivation of EGFR/ HER2 signalling by several exogenous EGFR ligands (Hutcheson et al 2003, Nicholson et al 2004c).…”

Section: Introductionmentioning

confidence: 80%

“…Exposure of MCF-7 cells to the ERBB ligand heregulin, which markedly upregulates MAPK and AKT signalling, is associated with lack of response to all endocrine manipulation (Nicholson et al 2004c). Similarly, secondline response to faslodex in our acquired TAMR cells can be abrogated by further hyperactivation of EGFR/ HER2 signalling by several exogenous EGFR ligands (Hutcheson et al 2003, Nicholson et al 2004c). Thus, extreme growth factor signalling not only promotes experimental de novo tamoxifen resistance in ER + cells, but also, under certain (as yet poorly defined) conditions, may be able to signal in an ER-independent manner and promote ER + endocrine insensitivity.…”

Section: Introductionmentioning

confidence: 80%

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Epidermal growth factor receptor/HER2/insulin-like growth factor receptor signalling and oestrogen receptor activity in clinical breast cancer

Gee

Robertson²,

Gutteridge³

et al. 2005

Endocr Relat Cancer

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189

173

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Breast cancer models of acquired tamoxifen resistance, oestrogen receptor (ER) + /ER -de novo resistance and gene transfer studies cumulatively demonstrate the increased importance of growth factor receptor signalling, notably the epidermal growth factor receptor (EGFR)/HER2, in tamoxifen resistance. Our recent in vitro studies also suggest that EGFR signalling productively cross-talks with insulin-like growth factor receptor (IGF-1R) and, where present, activates ER on key AF-1 serine residues to facilitate acquired tamoxifen-resistant growth. This paper presents our immunohistochemical evidence that EGFR/HER2 signalling (i.e. transforming growth factor (TGF)a, EGFR and HER2 expression; phosphorylation of EGFR, HER2 and ERK1/2 MAP kinase) is also prominent in clinical de novo resistant and modestly increased in acquired tamoxifen-resistant states, suggesting that anti-EGFR/HER2 strategies may prove valuable treatments. Primary breast cancer samples employed were obtained for (1) patients subsequently treated with tamoxifen for advanced disease where endocrine response and survival data were available and (2) ER + elderly patients during tamoxifen response and relapse. We also present our clinical immunohistochemical findings that IGF-1R expression, its phosphorylation on tyrosine 1316, and also phosphorylation on serine 118 of ER are not only prominent in ER + tamoxifen-responsive disease, but are also detectable in ER + de novo and acquired tamoxifen-resistant breast cancer, where there is evidence of EGFR/ER cross-talk. Our data suggest that agents to deplete effectively ER or IGF-1R signalling may be of value in treating ER + de novo/acquired tamoxifen resistance in addition to tamoxifenresponsive disease in vivo. IGF-1R inhibitors may also prove valuable in ER -patients, since considerable IGF-1R signalling activity was apparent within 50% of such tumours.Endocrine-Related Cancer (2005) 12 S99-S111

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Section: Introductionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 80%

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Epidermal growth factor receptor/HER2/insulin-like growth factor receptor signalling and oestrogen receptor activity in clinical breast cancer

Gee

Robertson²,

Gutteridge³

et al. 2005

Endocr Relat Cancer

Self Cite

189

173

View full text Add to dashboard Cite

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“…Suppression of ERa expression through the mechanisms that we have above described might have a role in this phenomenon. In this regard, Nicholson et al (2004) have recently reported that fulvestrantresistant cells lost expression of ERa following prolonged exposure to anti-estrogen. Expression of ERa did not resume in fulvestrant-resistant cells following removal of the drug, and it was associated with the development of an estrogen-independent phenotype.…”

Section: Growth Factor Signaling In Resistance To Endocrine Therapymentioning

confidence: 99%

Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer

Normanno

Maïo

Maio

et al. 2005

Endocr Relat Cancer

257

224

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Tamoxifen has been the mainstay of hormonal therapy in both early and advanced breast cancer patients for approximately three decades. The availability of novel compounds such as aromatase inhibitors (AIs) and fulvestrant, with different mechanism of action, is changing the scenario of endocrine treatment of postmenopausal breast cancer patients. In this review article, we have summarized the current knowledge of the mechanisms of resistance to endocrine therapy, in order to derive information that might be useful for therapeutic intervention. We propose that resistance to endocrine therapy is a progressive, step-wise phenomenon induced by the selective pressure of hormonal agents, which leads breast cancer cells from an estrogen-dependent, responsive to endocrine manipulation phenotype to a non-responsive phenotype, and eventually to an estrogenindependent phenotype. In particular, evidence suggests for each 'action' introduced to block estrogen stimulation of breast cancer cells (i.e. treatment with anti-estrogen), there are one or more corresponding 'reactions' that tumor cells can use to escape our attempts to block their growth: estrogen hypersensitivity associated with increased transcriptional activity of estrogen receptor a (ERa) and/or increased non-genomic activity of ERa, estrogen supersensitivity, increased growth factor signaling, suppression of ERa expression and finally estrogen independence. Activation of growth factor signaling is involved in each step of this phenomenon, and might ultimately substitute estrogen in sustaining the growth and the survival of breast cancer cells. In this respect, results of pre-clinical and clinical studies with AIs, fulvestrant and signaling inhibitors sustain this hypothesis. More importantly, the knowledge of the mechanisms involved in the resistance of breast cancer cells to endocrine therapy offers potential for novel therapeutic strategies.

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“…To address this question, studies have been undertaken to investigate longterm estrogen deprivation (LTED), since AIs function to effectively block the synthesis of estrogens. LTED cells have been generated in Dr. R. Santen's, Dr. M. Dowsett's, Dr. R. Nicholson's and Dr. A. Brodie's laboratories [31][32][33][34]. The key findings from these laboratories have been reviewed in a recent report [35].…”

Section: Acquired Resistancementioning

confidence: 99%

New experimental models for aromatase inhibitor resistance

Chen

Masri

Hong

et al. 2007

The Journal of Steroid Biochemistry and Molecular Biology

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Clinical trials have demonstrated the importance of aromatase inhibitor (AI) therapy in the effective treatment of hormone-dependent breast cancers. In contrast to tamoxifen, an antagonist of the estrogen receptor (ER), AIs have shown to be better tolerated along with decreased recurrence rates of the disease. Currently, three third-generation AIs are being used: exemestane, letrozole and anastrozole. Our laboratory is attempting to understand several aspects of aromatase inhibitor functionality. In this paper, we first review recent findings from our structure-function studies of aromatase as well as the molecular characterization of the interaction between AIs and aromatase. Based on these studies, we propose new evidence for the interaction of letrozole and exemestane with aromatase. In addition, we will discuss recent results generated from our AI-resistant cell lines. Our laboratory has generated MCF-7aro cells that are resistant to letrozole, anastrozole, exemestane and tamoxifen. Basic functional characterization of aromatase and ERα in these resistant cell lines has been done and microarray analysis has been employed in order to better understand the mechanism responsible for AI resistance on a genome-wide scale. The results generated so far suggest the presence of at least four types of resistant cell lines. Overall, the information presented in this paper supplements our understanding of AI function, and such information can be valuable for the development of treatment strategies against AI resistant breast cancers.

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Growth factor-driven mechanisms associated with resistance to estrogen deprivation in breast cancer: new opportunities for therapy

Cited by 86 publications

References 107 publications

Epidermal growth factor receptor/HER2/insulin-like growth factor receptor signalling and oestrogen receptor activity in clinical breast cancer

Epidermal growth factor receptor/HER2/insulin-like growth factor receptor signalling and oestrogen receptor activity in clinical breast cancer

Mechanisms of endocrine resistance and novel therapeutic strategies in breast cancer

New experimental models for aromatase inhibitor resistance

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