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1.
Breast Cancer Res ; 13(2): R29, 2011 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-21396094

RESUMEN

INTRODUCTION: We have previously reported that induction of epidermal growth factor receptor and ErbB2 in response to antihormonal agents may provide an early mechanism to allow breast cancer cells to evade the growth-inhibitory action of such therapies and ultimately drive resistant cell growth. More recently, the other two members of the ErbB receptor family, ErbB3 and ErbB4, have been implicated in antihormone resistance in breast cancer. In the present study, we have investigated whether induction of ErbB3 and/or ErbB4 may provide an alternative resistance mechanism to antihormonal action in a panel of four oestrogen receptor (ER)-positive breast cancer cell lines. METHODS: MCF-7, T47D, BT474 and MDAMB361 cell lines were exposed to fulvestrant (100 nM) for seven days, and effects on ErbB3/4 expression and signalling, as well as on cell growth, were assessed. Effects of heregulin ß1 (HRGß1) were also examined in the absence and presence of fulvestrant to determine the impact of ER blockade on the capacity of this ErbB3/4 ligand to promote signalling and cell proliferation. RESULTS: Fulvestrant potently reduced ER expression and transcriptional activity and significantly inhibited growth in MCF-7, T47D, BT474 and MDAMB361 cells. However, alongside this inhibitory activity, fulvestrant also consistently induced protein expression and activity of ErbB3 in MCF-7 and T47D cells and ErbB4 in BT474 and MDAMB361 cell lines. Consequently, fulvestrant treatment sensitised all cell lines to the actions of the ErbB3/4 ligand HRGß1 with enhanced ErbB3/4-driven signalling activity, reexpression of cyclin D1 and significant increases in cell proliferation being observed when compared to untreated cells. Indeed, in T47D and MDAMB361 HRGß1 was converted from a ligand having negligible or suppressive growth activity into one that potently promoted cell proliferation. Consequently, fulvestrant-mediated growth inhibition was completely overridden by HRGß1 in all four cell lines. CONCLUSIONS: These findings suggest that although antihormones such as fulvestrant may have potent acute growth-inhibitory activity in ER-positive breast cancer cells, their ability to induce and sensitise cells to growth factors may serve to reduce and ultimately limit their inhibitory activity.


Asunto(s)
Receptores ErbB/metabolismo , Estradiol/análogos & derivados , Neurregulina-1/metabolismo , Receptor ErbB-3/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ciclina D1/biosíntesis , Resistencia a Antineoplásicos , Receptores ErbB/biosíntesis , Estradiol/farmacología , Moduladores de los Receptores de Estrógeno/farmacología , Femenino , Fulvestrant , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Receptor ErbB-4 , Receptores de Estrógenos/metabolismo , Transducción de Señal/efectos de los fármacos
2.
Endocr Relat Cancer ; 13 Suppl 1: S89-97, 2006 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-17259562

RESUMEN

Aberrant epidermal growth factor receptor (EGFR) signalling, a key feature of a variety of human malignancies, can drive a range of mechanisms underlying tumour growth and progression, including increased cell proliferation, angiogenesis, metastasis and decreased apoptosis. Anti-EGFR therapies, as monotherapies and in combination with chemotherapy, have proved effective in inhibiting these processes both in the clinical and in the preclinical settings. However, only a small cohort of patients have derived significant benefit from this therapy, with both de novo and acquired resistance to these agents evident in a number of recent studies. If we are to improve the effectiveness of such targeted therapies, then there is an urgent need to understand the resistance mechanisms. Here, we describe both non-genomic and genomic mechanisms of resistance to the selective EGFR tyrosine kinase inhibitor gefitinib (IRESSA), which we have identified initially in an EGFR-positive tamoxifen-resistant MCF-7 breast cancer cell line, but more recently in other EGFR-positive cancer types. Importantly, we show that gefitinib, in common with anti-hormonal agents, is not a passive bystander in the cellular response to drug treatment, but plays an active role in promoting signalling pathways that serve to limit its anti-tumour activity and maintain the cellular cohort from which acquired resistance can ultimately evolve. These findings indicate that inductive signalling is an important determinant of response to EGFR-targeted therapies and deciphering such pathways may provide us with the opportunity to design more effective strategies to combat resistance mechanisms and improve response to initial therapy.


Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Carcinoma/tratamiento farmacológico , Carcinoma/genética , Resistencia a Antineoplásicos/genética , Receptores ErbB/antagonistas & inhibidores , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Animales , Evaluación Preclínica de Medicamentos , Gefitinib , Humanos , Proteínas Sustrato del Receptor de Insulina , Proteína Oncogénica v-akt/genética , Fosfatidilinositol 3-Quinasas/genética , Fosfoproteínas/fisiología , Quinazolinas/uso terapéutico , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética
3.
Eur J Med Chem ; 56: 246-53, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22995819

RESUMEN

The tetrahydroazepinone pharmacophore is a component of many interesting compounds, including several marine natural products, with anti-cancer properties. The synthesis and biological evaluation of a novel series of pyrroloazepinone and indoloazepinone oximes is reported. These compounds showed promising growth inhibition activity against four human cancer cell lines but did not significantly inhibit the cell cycle regulator cyclin dependent kinase 2. The most active compounds in this series displayed improved anti-proliferative activity over the related synthetic indoloazepine kenpaullone. The structure activity relationships exhibited by the azepinone pharmacophore suggests several novel lead compounds for anti-cancer drug discovery.


Asunto(s)
Antineoplásicos/farmacología , Azepinas/química , Azepinas/farmacología , Productos Biológicos/farmacología , Indoles/farmacología , Oximas/farmacología , Pirroles/química , Pirroles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Azepinas/síntesis química , Productos Biológicos/síntesis química , Productos Biológicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Indoles/síntesis química , Indoles/química , Células MCF-7 , Estructura Molecular , Oximas/síntesis química , Oximas/química , Pirroles/síntesis química , Relación Estructura-Actividad
4.
PLoS One ; 7(7): e40466, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22808167

RESUMEN

In the present study, we have taken the novel approach of using an in vitro model representative of tamoxifen-withdrawal subsequent to clinical relapse to achieve a greater understanding of the mechanisms that serve to maintain the resistant-cell phenotype, independent of any agonistic impact of tamoxifen, to identify potential novel therapeutic approaches for this disease state. Following tamoxifen withdrawal, tamoxifen-resistant MCF-7 cells conserved both drug resistance and an increased basal rate of proliferation in an oestrogen deprived environment, despite reduced epidermal growth-factor receptor expression and reduced sensitivity to gefitinib challenge. Although tamoxifen-withdrawn cells retained ER expression, a sub-set of ER-responsive genes, including pS2 and progesterone receptor (PgR), were down-regulated by promoter DNA methylation, as confirmed by clonal bisulphite sequencing experiments. Following promoter demethylation with 5-Azacytidine (5-Aza), the co-addition of oestradiol (E2) restored gene expression in these cells. In addition, 5-Aza/E2 co-treatment induced a significant anti-proliferative effect in the tamoxifen-withdrawn cells, in-contrast to either agent used alone. Microarray analysis was undertaken to identify genes specifically up regulated by this co-treatment. Several anti-proliferative gene candidates were identified and their promoters were confirmed as more heavily methylated in the tamoxifen resistant vs sensitive cells. One such gene candidate, growth differentiation factor 15 (GDF15), was carried forward for functional analysis. The addition of 5-Aza/E2 was sufficient to de-methylate and activate GDF15 expression in the tamoxifen resistant cell-lines, whilst in parallel, treatment with recombinant GDF15 protein decreased cell survival. These data provide evidence to support a novel concept that long-term tamoxifen exposure induces epigenetic silencing of a cohort of oestrogen-responsive genes whose function is associated with negative proliferation control. Furthermore, reactivation of such genes using epigenetic drugs could provide a potential therapeutic avenue for the management of tamoxifen-resistant breast cancer.


Asunto(s)
Neoplasias de la Mama/genética , Resistencia a Antineoplásicos/genética , Estrógenos/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Silenciador del Gen/efectos de los fármacos , Tamoxifeno/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Azacitidina/farmacología , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Metilación de ADN/efectos de los fármacos , Metilación de ADN/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Receptores ErbB/metabolismo , Femenino , Gefitinib , Genes Relacionados con las Neoplasias/genética , Factor 15 de Diferenciación de Crecimiento/farmacología , Humanos , Células MCF-7 , Quinazolinas/farmacología , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Proteínas Recombinantes/farmacología , Factor Trefoil-1 , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo
5.
Horm Mol Biol Clin Investig ; 5(2): 67-77, 2011 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-25961242

RESUMEN

Using MCF7 breast cancer cells, it has been shown that antihormones promote expression/activity of oestrogen-repressed tyrosine kinases, notably EGFR, HER2 and Src. These inductive events confer responsiveness to targeted inhibitors (e.g., gefitinib, trastuzumab, saracatinib). We observed that these antihormone-induced phenomena are common to ER+HER2- and ER+HER2+ breast cancer models in vitro, where targeting of EGFR, HER2 or Src alongside antihormone improves antitumour response and delays/prevents endocrine resistance. Such targeted inhibitors also subvert acquired endocrine resistant cells which retain increased EGFR, HER2 and Src (e.g., TAMR and FASR models derived after 6-12 months of tamoxifen or Faslodex treatment). Thus, antihormone-induced tyrosine kinases comprise "compensatory signalling" crucial in limiting maximal initial antihormone response and subsequently driving acquired resistance in vitro. However, despite such convincing preclinical findings from our group and others, clinical trials examining equivalent antigrowth factor strategies have proved relatively disappointing. Our new studies deciphering underlying causes reveal that further antihormone-promoted events could be pivotal in vivo. Firstly, Faslodex induces HER3 and HER4 which sensitise ER+ cells to heregulin, a paracrine growth factor that overcomes endocrine response and diminishes antitumour effect of agents targeting EGFR, HER2 or Src alongside antihormone. Secondly, extended antihormone exposure (experienced by ER+ cells prior to adjuvant clinical relapse) can "reprogramme" the compensatory kinase profile in vitro, hindering candidate antigrowth factor targeting of endocrine resistance. Faslodex resistant cells maintained with this antihormone for 3 years in vitro lose EGFR/HER2 dependency, gaining alternative mitogenic/invasion kinases. Deciphering these previously unrecognised antihormone-induced events could provide superior treatments to control endocrine relapse in the clinic.

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