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1.
Breast Cancer Res Treat ; 152(3): 499-508, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26133921

RESUMO

Resistance to aromatase inhibitors (AIs) involves increased HER2. One mechanism by which HER2 may mediate resistance is through expansion of the tumor initiating cell (TIC) population. This study investigates whether combining all-trans retinoic acid (ATRA) and histone deacetylase inhibitor entinostat (ENT) can inhibit TICs and HER2 in AI-resistant cells and tumors. Modulation of cell viability and HER2 expression were assessed in AI-resistant cells treated with ATRA + ENT. Letrozole-resistant LTLT-Ca cells treated with ATRA + ENT were assayed for changes in TIC characteristics, such as TIC markers (BCRP, ALDH, and BMI-1), side population (SP), and mammosphere formation. Xenograft tumors of MCF-7Ca cells made resistant to letrozole were treated with ATRA, ATRA + letrozole, ATRA + ENT, or ATRA + ENT + letrozole. Resulting tumors were assayed for changes in TIC characteristics. Patient samples taken pre- and post-AI treatment were analyzed for changes in ERα and HER2 protein expression. Treatment with ATRA + ENT reduced HER2 expression and viability (P < 0.001) in AI-resistant cells, as well as decreased SP (P < 0.0001), mammosphere formation (P < 0.01), and expression of TIC molecular markers (P < 0.01) in LTLT-Ca. A reduction in tumor growth rate was observed in mice treated with ENT + ATRA + letrozole when compared to mice treated with single agents (P < 0.0001) or ENT + ATRA (P = 0.02). Decreased TIC characteristics, including mammosphere formation (P < 0.05), were observed in tumors from the triple combination. An increase in HER2 and downregulation in ERα protein expression was observed in patients upon resistance to AI (P < 0.005). These studies indicate that the combination of ATRA and ENT inhibits the TIC population of AI-resistant cells and may be effective in reducing tumor recurrence.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Receptor ErbB-2/metabolismo , Animais , Inibidores da Aromatase/farmacologia , Benzamidas/administração & dosagem , Benzamidas/farmacologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Inibidores de Histona Desacetilases/administração & dosagem , Humanos , Letrozol , Camundongos Nus , Nitrilas/farmacologia , Piridinas/administração & dosagem , Piridinas/farmacologia , Tretinoína/administração & dosagem , Triazóis/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Breast Cancer Res Treat ; 138(3): 699-708, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23508762

RESUMO

Despite significant improvement in the treatment outcome of hormone responsive postmenopausal breast cancer, some patients eventually acquire resistance to aromatase inhibitors (AIs). Using our MCF-7Ca xenograft model, we observed that although AIs such as anastrozole initially inhibit tumor growth effectively, tumors eventually began to grow. Our previous data show that anastrozole-resistant tumors upregulate growth factor receptor pathways as they adapt to grow in the low estrogen environment. Therefore, in the current study, we investigated the effect of inhibiting the growth factor receptor pathways with a MEK-1/2 inhibitor selumetinib (AZD6244, ARRY-142866). We treated the mice with anastrozole-resistant tumors with selumetinib alone or in combination with anastrozole. MCF-7Ca cells were inoculated sc into ovariectomized athymic nude mice supplemented throughout the experiment with androstenedione (100 µg/day), the substrate for aromatase conversion to estrogen. Once the tumors reached a measurable size (~300 mm(3)), the mice were treated with anastrozole (200 µg/day), supplemented with androstenedione (Δ(4)A). The tumors in the anastrozole group doubled in volume after 6 weeks, at which time the animals were regrouped to receive the following treatments: (i) anastrozole, (ii) anastrozole withdrawal (Δ(4)A alone), (iii) selumetinib (25 mg/kg/d, bid, po), and (iv) selumetinib + anastrozole, (n = 10 mice/group). The treatments were given for 6 weeks (till week 12) and then the mice were euthanized, the tumors were collected and analyzed. The tumors of mice treated with selumetinib + anastrozole had significantly lower growth rates than those treated with single agents (p = 0.008). Western blot analysis of the tumors showed that treatment with anastrozole resulted in upregulation of proteins in the growth factor receptor cascade such as p-mTOR, pAkt, pMEK, and pMAPK. This was accompanied by downregulation of ERα protein, consistent with previous findings. The treatment of mice with selumetinib resulted in downregulation of activated MAPK, along with p-mTOR, which likely resulted in upregulation of ERα. Our results suggest that inhibition of the growth factor receptor pathway with selumetinib can reverse anastrozole resistance.


Assuntos
Benzimidazóis/farmacologia , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Nitrilas/farmacologia , Triazóis/farmacologia , Anastrozol , Androstenodiona/farmacologia , Animais , Antineoplásicos Hormonais/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Inibidores da Aromatase/farmacologia , Benzimidazóis/administração & dosagem , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , MAP Quinase Quinase 1/antagonistas & inibidores , Camundongos , Camundongos Nus , Nitrilas/administração & dosagem , Ovariectomia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Triazóis/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
3.
J Steroid Biochem Mol Biol ; 202: 105697, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32461092

RESUMO

Treatment of hormone sensitive breast cancer tumors with endocrine therapy such as antiestrogens or aromatase inhibitors has improved the outcome significantly. Studies including our own have shown that downregulation of ERα with pure antiestrogen fulvestrant in combination with aromatase inhibitors may prolong responsiveness of the tumors to endocrine therapy. Fulvestrant has been studied as second line or first line treatment for post-menopausal hormone receptor positive breast cancers as a single agent or in combination with AIs. Studies have also suggested that further escalation of dose may improve benefit. However, dose escalation of fulvestrant, which is administered via intramuscular injection, is difficult due to its poor solubility. To overcome this shortcoming of an injectable drug, a novel orally active antiestrogen, AZD9496 was developed. In addition to being orally active, AZD9496 is designed as a selective ERα downregulator (SERD). In the current study, we compared the effect of AZD9496 and fulvestrant on the growth of MCF-7Ca (human estrogen receptor positive MCF-7 cells stably transfected with human placental aromatase gene) xenografts grown in ovariectomized athymic nude mice. AZD9496 was also compared to fulvestrant in vitro as a single agent or in combination with anastrozole. Our current study shows that AZD9496 is equally effective as fulvestrant at controlling the growth of hormone sensitive human breast cancer tumors. Similar to fulvestrant, AZD9496 inhibits cellular aromatase activity through ERα mediated signaling. However, unlike fulvestrant, combination of AZD9496 with anastrozole did not produce increased tumor inhibition. Our results show that AZD9496 was significantly better at inhibiting cellular aromatase which contributed to its anticancer activity. Next, we measured the effect of AZD9496 on the mouse uterus. Uterine weight of mice treated with AZD9496 was significantly lower than that for mice treated with androstenedione. This reduction in uterine weight was due to AZD9496 mediated inhibition of aromatase activity and not a direct effect on uterine ERα expression. We also observed that anti-cancer efficacy of AZD9496 depended on its ability to inhibit cellular aromatase. These results suggest that AZD9496 may be a better alternative to fulvestrant due to its selectivity for mammary ER and ability to inhibit aromatase in addition of downregulating ERα that can be obtained upon oral administration. As such, AZD9496 may prove to be a better option than fulvestrant for the treatment of hormone sensitive human breast cancer.


Assuntos
Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Cinamatos/uso terapêutico , Indóis/uso terapêutico , Neoplasias Mamárias Experimentais/tratamento farmacológico , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Anastrozol/farmacologia , Anastrozol/uso terapêutico , Animais , Antineoplásicos Hormonais/farmacologia , Antineoplásicos Hormonais/uso terapêutico , Aromatase/metabolismo , Inibidores da Aromatase/farmacologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Cinamatos/farmacologia , Antagonistas do Receptor de Estrogênio/farmacologia , Antagonistas do Receptor de Estrogênio/uso terapêutico , Receptor alfa de Estrogênio , Feminino , Fulvestranto/farmacologia , Fulvestranto/uso terapêutico , Humanos , Indóis/farmacologia , Neoplasias Mamárias Experimentais/metabolismo , Camundongos Nus , Pós-Menopausa , Moduladores Seletivos de Receptor Estrogênico/farmacologia
4.
J Steroid Biochem Mol Biol ; 108(1-2): 1-7, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17942301

RESUMO

Since most breast cancers occur in postmenopausal women and are hormone dependent, we developed a model system that mimics this situation. In this model, tumors of human estrogen receptor (ER) positive breast cancer cells stably transfected with aromatase (Ac-1) are grown in immune-compromised mice. Using this model we have explored a number of therapeutic strategies to maximize the antitumor efficacy of antiestrogens (AEs) and aromatase inhibitors (AIs). This intratumoral aromatase xenograft model has proved accurate in predicting the outcome of several clinical trials. In this current study we compared the effect of an AE toremifene and steroidal AI atamestane, alone or in combination, on growth of hormone-dependent human breast cancer. We have also compared toremifene plus atamestane combination with tamoxifen in this study. The growth of Ac-1 cells was inhibited by tamoxifen, toremifene and atamestane in vitro with IC(50) values of 1.8+/-1.3 microM, 1+/-0.3 microM and 60.4+/-17.2 microM, respectively. The combination of toremifene plus atamestane was found to be better than toremifene or atamestane alone in vitro. The effect of this combination was then studied in vivo using Ac-1 xenografts grown in ovariectomized female SCID mice. The mice were injected with toremifene (1000 microg/day), atamestane (1000 microg/day), tamoxifen (100 microg/day), or the combination of toremifene plus atamestane. In this study, our results indicate that the combination of toremifene plus atamestane was as effective as toremifene or tamoxifen alone but may not provide any additional benefit over toremifene alone or tamoxifen alone.


Assuntos
Androstenodiona/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aromatase/genética , Neoplasias da Mama/tratamento farmacológico , Modelos Animais de Doenças , Toremifeno/administração & dosagem , Androstenodiona/administração & dosagem , Animais , Antineoplásicos Hormonais/administração & dosagem , Aromatase/metabolismo , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Camundongos , Camundongos SCID , Prognóstico , Transfecção , Resultado do Tratamento , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Cancer Res ; 66(15): 7775-82, 2006 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-16885381

RESUMO

Previous work has shown that androgens inhibit breast cancer cells and tumor growth. On the other hand, androgens can be converted to mitogenic estrogens by aromatase in breast cancer cells. Here, we report that androgens, such as the aromatizable androstenedione and the non-aromatizable 5alpha-dihydrotestosterone, inhibit MCF-7 cell proliferation. This effect is observed only in the absence or at a low concentration of estrogens and is evident in cells with low aromatase activity. Growth of a new aromatase stably transfected MCF-7 cell line (Ac1) was stimulated by conversion of androstenedione into estrogens and was sensitive to aromatase inhibitors. We show that blockade of the androgen receptor (AR) in these cells by the antiandrogen casodex or by the anti-AR small interfering RNA inhibited the antiproliferative effect of dihydrotestosterone and letrozole (aromatase inhibitor). We also show that suppression of the estrogen-induced antiapoptotic protein Bcl-2 may be involved in the antiproliferative effects of androgens and letrozole. These effects can be reversed by casodex. In conclusion, the results suggest that aromatase inhibitors may exert their antiproliferative effect not only by reducing the intracellular production of estrogens but also by unmasking the inhibitory effect of androgens acting via the AR.


Assuntos
Androgênios/fisiologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Neoplasias Hormônio-Dependentes/patologia , Nitrilas/farmacologia , Triazóis/farmacologia , Antagonistas de Receptores de Andrógenos , Androgênios/farmacologia , Androstenodiona/farmacologia , Aromatase/genética , Aromatase/metabolismo , Neoplasias da Mama/genética , Processos de Crescimento Celular/efeitos dos fármacos , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Di-Hidrotestosterona/antagonistas & inibidores , Di-Hidrotestosterona/farmacologia , Estradiol/farmacologia , Receptor alfa de Estrogênio/biossíntese , Humanos , Letrozol , Neoplasias Hormônio-Dependentes/genética , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , RNA Interferente Pequeno/genética , Receptores Androgênicos/biossíntese , Transfecção
6.
Cancer Res ; 65(9): 3903-10, 2005 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-15867390

RESUMO

To study the long-term effects of estrogen deprivation on breast cancer, MCF-7Ca human estrogen receptor-positive breast cancer cells stably transfected with human aromatase gene were cultured in the steroid-depleted medium for 6 to 8 months until they had acquired the ability to grow. Proliferation of these cells (UMB-1Ca) was accompanied by increased expression of human epidermal growth factor receptor 2, increased activation of AKT through phosphorylation at Ser473 and Thr308, and increased invasion compared with parental MCF-7Ca cells. Estrogen receptor expression was also increased 5-fold. Although growth was inhibited by the antiestrogen fulvestrant, the IC50 was 100-fold higher than for parental MCF-7Ca cells. Aromatase inhibitor letrozole also inhibited growth at 10,000-fold higher concentration than required for MCF-7Ca cells, whereas anastrozole, exemestane, formestane, and tamoxifen were ineffective at 100 nmol/L. Growth of UMB-1Ca cells was inhibited by phosphatidylinositol 3-kinase inhibitor wortmannin (IC50 approximately 25 nmol/L) and epidermal growth factor receptor kinase inhibitor gefitinib (ZD 1839; IC50 approximately 10 micromol/L) whereas parental MCF-7Ca cells were insensitive to these agents. Concomitant treatment of UMB-1Ca cells with the signal transduction inhibitors and anastrozole and tamoxifen restored their growth inhibitory effects. These studies show that estrogen deprivation results in up-regulation of growth factor signaling pathways, which leads to a more aggressive and hormone refractory phenotype. Cross-talk between ER and growth factor signaling was evident as inhibition of these pathways could restore estrogen responsiveness to these cells.


Assuntos
Neoplasias da Mama/patologia , Estrogênios/deficiência , Neoplasias Hormônio-Dependentes/patologia , Proteínas Serina-Treonina Quinases/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Receptores de Estrogênio/fisiologia , Receptores de Fatores de Crescimento/fisiologia , Neoplasias da Mama/enzimologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Ativação Enzimática , Estrogênios/fisiologia , Humanos , Invasividade Neoplásica , Neoplasias Hormônio-Dependentes/enzimologia , Neoplasias Hormônio-Dependentes/metabolismo , Proteínas Proto-Oncogênicas c-akt , Receptor Cross-Talk/fisiologia , Transdução de Sinais/fisiologia , Regulação para Cima
7.
Mol Cancer Ther ; 14(11): 2642-52, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26310543

RESUMO

Heregulin-driven ERBB3 signaling has been implicated as a mechanism of resistance to cytotoxic and antiendocrine therapies in preclinical breast cancer models. In this study, we evaluated the effects of seribantumab (MM-121), a heregulin-blocking anti-ERBB3 monoclonal antibody, alone and in combination with the aromatase inhibitor letrozole, on cell signaling and tumor growth in a preclinical model of postmenopausal estrogen receptor-positive (ER(+)) breast cancer. In vitro, heregulin treatment induced estrogen receptor phosphorylation in MCF-7Ca cells, and long-term letrozole-treated (LTLT-Ca) cells had increased expression and activation levels of EGFR, HER2, and ERBB3. Treatment with seribantumab, but not letrozole, inhibited basal and heregulin-mediated ERBB receptor phosphorylation and downstream effector activation in letrozole-sensitive (MCF-7Ca) and -refractory (LTLT-Ca) cells. Notably, in MCF-7Ca-derived xenograft tumors, cotreatment with seribantumab and letrozole had increased antitumor activity compared with letrozole alone, which was accompanied by downregulated PI3K/MTOR signaling both prior to and after the development of resistance to letrozole. Moreover, the addition of an MTOR inhibitor to this treatment regimen did not improve antitumor activity and was not well tolerated. Our results demonstrate that heregulin-driven ERBB3 signaling mediates resistance to letrozole in a preclinical model of ER(+) breast cancer, suggesting that heregulin-expressing ER(+) breast cancer patients may benefit from the addition of seribantumab to antiendocrine therapy.


Assuntos
Anticorpos Monoclonais/farmacologia , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Nitrilas/farmacologia , Receptor ErbB-3/antagonistas & inibidores , Triazóis/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais Humanizados , Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Humanos , Immunoblotting , Letrozol , Camundongos Endogâmicos BALB C , Camundongos Nus , Neuregulina-1/farmacologia , Ovariectomia , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Receptor ErbB-3/imunologia , Receptor ErbB-3/metabolismo , Receptores de Estrogênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
8.
Curr Pharm Des ; 20(42): 6575-83, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25341934

RESUMO

Aromatase inhibitors (AIs) have become one of the mainstays of treatment of postmenopausal women with hormone receptorpositive breast cancer. However, acquired resistance to treatment continues to be a significant clinical challenge. There is increasing evidence from preclinical studies that activation of growth factor signaling pathways, as well as cross-talk between these pathways and estrogen receptor-alpha signaling pathways are important mechanisms that contribute to AI resistance. These preclinical studies have been the foundation for multiple randomized clinical trials that have evaluated combination targeted therapy in patients with advanced breast cancer. While the clinical benefit observed in these trials has been variable, the preclinical studies were successful in predicting clinical outcomes. This review focuses on mechanisms of acquired AI resistance and describes preclinical studies that have evaluated combination targeted therapy to overcome AI resistance, as well as clinical trials that have translated this information to the clinical setting.


Assuntos
Inibidores da Aromatase/farmacologia , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Antineoplásicos Hormonais/farmacologia , Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Terapia Combinada , Humanos
9.
Mol Cancer Ther ; 12(12): 2804-16, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24092810

RESUMO

We previously showed that in innately resistant tumors, silencing of the estrogen receptor (ER) could be reversed by treatment with a histone deacetylase (HDAC) inhibitor, entinostat. Tumors were then responsive to aromatase inhibitor (AI) letrozole. Here, we investigated whether ER in the acquired letrozole-resistant tumors could be restored with entinostat. Ovariectomized athymic mice were inoculated with MCF-7Ca cells, supplemented with androstenedione (Δ(4)A), the aromatizable substrate. When the tumors reached about 300 mm(3), the mice were treated with letrozole. After initial response to letrozole, the tumors eventually became resistant (doubled their initial volume). The mice then were grouped to receive letrozole, exemestane (250 µg/d), entinostat (50 µg/d), or the combination of entinostat with letrozole or exemestane for 26 weeks. The growth rates of tumors of mice treated with the combination of entinostat with letrozole or exemestane were significantly slower than with the single agent (P < 0.05). Analysis of the letrozole-resistant tumors showed entinostat increased ERα expression and aromatase activity but downregulated Her-2, p-Her-2, p-MAPK, and p-Akt. However, the mechanism of action of entinostat in reversing acquired resistance did not involve epigenetic silencing but rather included posttranslational as well as transcriptional modulation of Her-2. Entinostat treatment reduced the association of the Her-2 protein with HSP-90, possibly by reducing the stability of Her-2 protein. In addition, entinostat also reduced Her-2 mRNA levels and its stability. Our results suggest that the HDAC inhibitor may reverse letrozole resistance in cells and tumors by modulating Her-2 expression and activity.


Assuntos
Antineoplásicos/farmacologia , Inibidores da Aromatase/farmacologia , Benzamidas/farmacologia , Resistencia a Medicamentos Antineoplásicos , Inibidores de Histona Desacetilases/farmacologia , Nitrilas/farmacologia , Piridinas/farmacologia , Receptor ErbB-2 , Triazóis/farmacologia , Animais , Antineoplásicos/administração & dosagem , Aromatase/genética , Aromatase/metabolismo , Inibidores da Aromatase/administração & dosagem , Benzamidas/administração & dosagem , Modelos Animais de Doenças , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSP90/metabolismo , Inibidores de Histona Desacetilases/administração & dosagem , Humanos , Letrozol , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células MCF-7 , Camundongos , Nitrilas/administração & dosagem , Piridinas/administração & dosagem , Estabilidade de RNA/efeitos dos fármacos , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Triazóis/administração & dosagem , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Steroids ; 76(8): 730-5, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21420993

RESUMO

Aromatase inhibitors (AIs) have become the front-line choice for treatment of ER+ breast cancer. Nevertheless, although patients are responsive initially, they may acquire resistance and become unresponsive to further treatment. In addition, approximately 25% of breast cancers do not express the estrogen receptor (ERα) and consequently, are innately resistant to endocrine therapy. We have investigated the mechanisms associated with this lack of treatment response using xenograft models. We found that in cells and tumors that acquired resistance to the AI letrozole therapy, expression of the ER was reduced whereas growth factor signally was enhanced, including a marked increase in HER2 expression. Treatment with trastuzumab (HER2 antibody) resulted in a significant down-regulation of HER2 and p-MAPK as well as restoration of ERα expression. Thus, when trastuzumab was added to letrozole treatment at the time of tumor progression, there was significantly prolonged tumor suppression compared to trastuzumab or letrozole alone. This suggests that inhibition of both HER2 and ERα signaling pathways are required for overcoming resistance and restoring treatment sensitivity. ER negative tumors are innately resistant to endocrine therapy. Repression of the ERα has been found to be due to epigenetic modifications such as increased methylation and histone deacetylation. We found that entinostat (ENT), a histone deacetylase inhibitor (HDACi), activated not only expression of ERα but also aromatase in MDA-MB-231 ER-negative breast cancer cells, resulting in their ability to respond to estrogen and letrozole. Treatment with ENT in combination with letrozole significantly reduced tumor growth rate in xenografts compared to control tumors (p<0.001). ENT plus letrozole treatment also prevented the colonization and growth of MDA-MB-231 cells in the lung with a significant reduction (p<0.03) in both visible and microscopic foci. These results provide a strong indication for possible use of AIs in combination with HDAC inhibitors for the treatment of ER-negative breast cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Inibidores da Aromatase/uso terapêutico , Aromatase/metabolismo , Neoplasias da Mama/tratamento farmacológico , Inibidores de Histona Desacetilases/uso terapêutico , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Aromatase/genética , Benzamidas/uso terapêutico , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Receptor alfa de Estrogênio/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Letrozol , Camundongos , Camundongos Nus , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Nitrilas/uso terapêutico , Fosforilação , Piridinas/uso terapêutico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Trastuzumab , Triazóis/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Horm Mol Biol Clin Investig ; 5(2): 97-103, 2011 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-25961245

RESUMO

Aromatase inhibitors (AIs) are first-line treatment for ER+ breast cancer. However, despite responses initially, some patients can eventually acquire resistance. Moreover, 25% of all breast cancer patients do not express the estrogen receptor (ERα) and are innately resistance. In tumors of mouse models with acquired AI letrozole resistance, expression of ERα was reduced whereas HER2/growth factor signaling was enhanced. Treatment of mice with trastuzumab (HER2 antibody) reduced HER2/p-MAPK but restored ERα expression. The addition of trastuzumab to letrozole treatment when tumors progressed resulted in significantly longer tumor suppression than these drugs alone. Thus, inhibition of both HER2 and ERα signaling pathways was necessary to overcome resistance. In ERα-negative tumors, the receptor has been shown to be silenced by epigenetic modifications. Treatment of MDA-MB-231 ER-negative tumors with a histone deacetylase inhibitor, entinostat (ENT) increased expression of ERα and also aromatase. When ENT was combined with letrozole, tumor growth rate was markedly reduced compared with control tumors. ENT plus letrozole treatment also prevented the colonization and growth of MDA-MB-231 cells in the lung with significant reduction in visible and microscopic foci. These novel strategies could improve treatment for patients with acquired and innate resistance to AIs.

12.
Cancer Res ; 71(5): 1893-903, 2011 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-21245100

RESUMO

Approximately 25% of breast cancers do not express the estrogen receptor-α (ERα) and consequently do not respond to endocrine therapy. In these tumors, ERα repression is often due to epigenetic modifications such as methylation and histone deacetylation. For this reason, we investigated the ability of the histone deacetylase inhibitor entinostat (ENT) to trigger reexpression of ERα and aromatase in breast cancer cells, with the notion that this treatment would restore sensitivity to the aromatase inhibitor (AI) letrozole. ENT treatment of tumor cells increased expression of ERα and aromatase, along with the enzymatic activity of aromatase, in a dose-dependent manner both in vitro and in vivo. Notably, ERα and aromatase upregulation resulted in sensitization of breast cancer cells to estrogen and letrozole. Tumor growth rate was significantly lower in tumor xenografts following treatment with ENT alone and in combination with letrozole than in control tumors (P > 0.001). ENT plus letrozole also prevented lung colonization and growth of tumor cells, with a significant reduction (P > 0.03) in both visible and microscopic foci. Our results show that ENT treatment can be used to restore the letrozole responsiveness of ER-negative tumors. More generally, they provide a strong rationale for immediate clinical evaluation of combinations of histone deacetylase and aromatase inhibitors to treat ER-negative and endocrine-resistant breast cancers.


Assuntos
Antineoplásicos/farmacologia , Aromatase/biossíntese , Benzamidas/farmacologia , Receptor alfa de Estrogênio/biossíntese , Nitrilas/farmacologia , Piridinas/farmacologia , Triazóis/farmacologia , Animais , Aromatase/efeitos dos fármacos , Western Blotting , Receptor alfa de Estrogênio/efeitos dos fármacos , Feminino , Humanos , Imuno-Histoquímica , Letrozol , Camundongos , Camundongos Nus , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
13.
J Steroid Biochem Mol Biol ; 118(4-5): 311-5, 2010 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-19778609

RESUMO

The IX International Aromatase Conference focused upon key developments in research related to the aromatase enzyme that had occurred since the last meeting. A session took place at the conclusion of conference discussing key areas for future research and issues currently facing researchers in the field. While significant progress on understanding structural elements of the enzyme and regulatory mechanisms of both the gene and protein provides an excellent basis for development of improved aromatase inhibitors and exploration of the important problem of aromatase inhibitor resistance, significant challenges remain. Increasing the speed with which findings are translated into clinical practice and finding an appropriate balance between basic and translational research were identified as areas which require further attention before the next meeting in 2010.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Aromatase/química , Aromatase/metabolismo , Neoplasias/tratamento farmacológico , Aromatase/genética , Humanos , Pesquisa Translacional Biomédica
14.
Cancer Res ; 68(9): 3516-22, 2008 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-18451180

RESUMO

Although the aromatase inhibitor anastrozole has been shown to be very effective in the treatment of hormone-dependent postmenopausal breast cancer, some patients with advanced disease will develop resistance to treatment. To investigate therapeutic strategies to overcome resistance to anastrozole treatment, we have used an intratumoral aromatase model that simulates postmenopausal breast cancer patients with estrogen-dependent tumors. Growth of the tumors in the mice was inhibited by both anastrozole and fulvestrant compared with the control tumors. Nevertheless, tumors had doubled in size at 5 weeks of treatment. We therefore investigated whether switching the original treatments to anastrozole or fulvestrant alone or the combination of anastrozole plus fulvestrant would reduce tumor growth. The results showed that the best strategy to reverse the insensitivity to anastrozole or fulvestrant is to combine the two agents. Additionally, the tumors treated with anastrozole plus fulvestrant from the beginning had only just doubled their size after 14 weeks of treatment, whereas the anastrozole and fulvestrant treatments alone resulted in 9- and 12-fold increases in tumor size, respectively, in the same time period. Anastrozole plus fulvestrant from the beginning or in sequence was associated with down-regulation of signaling proteins involved in the development of hormonal resistance such as insulin-like growth factor type I receptor beta, mitogen-activated protein kinase (MAPK), p-MAPK, AKT, mammalian target of rapamycin (mTOR), p-mTOR, and estrogen receptor alpha compared with tumors treated with anastrozole or fulvestrant alone. These results suggest that blocking the estrogen receptor and aromatase may delay or reverse the development of resistance to aromatase inhibitors in advanced breast cancer patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aromatase/metabolismo , Neoplasias da Mama/tratamento farmacológico , Estradiol/análogos & derivados , Nitrilas/administração & dosagem , Triazóis/administração & dosagem , Anastrozol , Animais , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/enzimologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Estradiol/administração & dosagem , Feminino , Fulvestranto , Humanos , Camundongos , Camundongos Nus , Tamanho do Órgão , Ovariectomia , Receptores de Fatores de Crescimento/metabolismo , Receptores de Fatores de Crescimento/fisiologia , Transdução de Sinais/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Células Tumorais Cultivadas , Útero/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Cancer Res ; 68(12): 4518-24, 2008 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-18559495

RESUMO

Using the intratumoral aromatase xenograft model, we have observed that despite long-lasting growth inhibition, tumors eventually begin to grow during continued letrozole treatment. In cells isolated from these long-term letrozole-treated tumors (LTLT-Ca), estrogen receptor-alpha (ERalpha) levels were decreased, whereas signaling proteins in the mitogen-activated protein kinase cascade were up-regulated along with human epidermal growth factor receptor 2 (Her-2). In the current study, we evaluated the effect of discontinuing letrozole treatment on the growth of letrozole-resistant cells and tumors. The cells formed tumors equally well in the absence or presence of letrozole and had similar growth rates. After treatment was discontinued for 6 weeks, letrozole was administered again. Marked tumor regression was observed with this second course of letrozole treatment. Similarly, in MCF-7Ca xenografts, a 6-week break in letrozole treatment prolonged the responsiveness of the tumors to letrozole. To understand the mechanisms of this effect, LTLT-Ca cells were cultured in the absence of letrozole for 16 weeks. The resulting cell line (RLT-Ca) exhibited properties similar to MCF-7Ca cells. The cell growth was inhibited by letrozole and stimulated by estradiol. The expression of phosphorylated mitogen-activated protein kinase (MAPK) was reduced and ERalpha and aromatase levels increased compared with LTLT-Ca cells and were similar to levels in MCF-7Ca cells. These results indicate that discontinuing treatment can reverse letrozole resistance. This could be a beneficial strategy to prolong responsiveness to aromatase inhibitors for patients with breast cancer.


Assuntos
Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Hormônio-Dependentes/tratamento farmacológico , Nitrilas/uso terapêutico , Triazóis/uso terapêutico , Animais , Antineoplásicos Hormonais/uso terapêutico , Aromatase/química , Aromatase/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Estradiol/metabolismo , Moduladores de Receptor Estrogênico/uso terapêutico , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Letrozol , Camundongos , Camundongos Nus , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neoplasias Hormônio-Dependentes/metabolismo , Neoplasias Hormônio-Dependentes/patologia , Ovariectomia , Fosforilação/efeitos dos fármacos , Receptor ErbB-2/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
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