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1.
Ann Clin Lab Sci ; 42(2): 135-9, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22585608

RESUMEN

We report a rare finding of two male breast cancer patients with HER2-positive breast cancer who also developed thyroid cancer. We reviewed 45 male breast cancer patients treated in our institution from 2003 to 2008. Only five male breast cancer patients were HER2-positive. In reviewing the published data, we found no cases of thyroid cancer and concurrent breast cancer in men. However, breast cancer and thyroid cancer have shown close association in women. This finding therefore provokes speculation as to whether we should investigate whether women with HER2-positive breast cancer are at a higher risk for thyroid cancer. Although this observation seems to be clinically prevalent, publications are sparse in clinical research areas linking thyroid cancer to breast cancer.


Asunto(s)
Academias e Institutos , Neoplasias de la Mama Masculina/complicaciones , Neoplasias de la Mama Masculina/patología , Receptor ErbB-2/metabolismo , Neoplasias de la Tiroides/complicaciones , Neoplasias de la Tiroides/patología , Anciano , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Coloración y Etiquetado
2.
J Clin Oncol ; 30(5): 533-8, 2012 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-22231041

RESUMEN

PURPOSE: Chemotherapy-induced amenorrhea is a serious concern for women undergoing cancer therapy. This prospective randomized trial evaluated the use of gonadotropin-releasing hormone (GnRH) analog triptorelin to preserve ovarian function in women treated with chemotherapy for early-stage breast cancer. PATIENTS AND METHODS: Premenopausal women age 44 years or younger were randomly assigned to receive either triptorelin or no triptorelin during (neo)adjuvant chemotherapy and were further stratified by age (< 35, 35 to 39, > 39 years), estrogen receptor status, and chemotherapy regimen. Objectives included the resumption of menses and serial monitoring of follicle-stimulating hormone (FSH) and inhibin A and B levels. RESULTS: Targeted for 124 patients with a planned 5-year follow-up, the trial was stopped for futility after 49 patients were enrolled (median age, 39 years; range, 21 to 43 years); 47 patients were treated according to assigned groups with four cycles of adriamycin plus cyclophosphamide alone or followed by four cycles of paclitaxel or six cycles of fluorouracil, epirubicin, and cyclophosphamide. Menstruation resumed in 19 (90%) of 21 patients in the control group and in 23 (88%) of 26 in the triptorelin group (P= .36). Menses returned after a median of 5.8 months (range, 1 to 19 months) after completion of chemotherapy in the triptorelin versus 5.0 months (range, 0 to 28 months) in the control arm (P= .58). Two patients (age 26 and 35 years at random assignment) in the control group had spontaneous pregnancies with term deliveries. FSH and inhibin B levels correlated with menstrual status. CONCLUSION: When stratified for age, estrogen receptor status, and treatment regimen, amenorrhea rates on triptorelin were comparable to those seen in the control group.


Asunto(s)
Amenorrea/prevención & control , Antineoplásicos Hormonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Fertilidad , Hormona Liberadora de Gonadotropina/agonistas , Terapia Neoadyuvante/métodos , Ovario/efectos de los fármacos , Pamoato de Triptorelina/uso terapéutico , Adulto , Amenorrea/inducido químicamente , Antineoplásicos Hormonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Biomarcadores/sangre , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Ciclofosfamida/efectos adversos , Supervivencia sin Enfermedad , Doxorrubicina/efectos adversos , Esquema de Medicación , Epirrubicina/efectos adversos , Femenino , Fertilidad/efectos de los fármacos , Fluorouracilo/efectos adversos , Hormona Folículo Estimulante/sangre , Estudios de Seguimiento , Hormona Liberadora de Gonadotropina/análogos & derivados , Humanos , Inhibinas/sangre , Menstruación , Estadificación de Neoplasias , Paclitaxel/efectos adversos , Tamoxifeno/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Pamoato de Triptorelina/administración & dosificación
3.
Ann Surg ; 254(2): 339-45, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21725233

RESUMEN

OBJECTIVE: To investigate the relationship between supply of subspecialty care and type of procedure preferentially performed for early stage breast cancer. BACKGROUND: Three surgical options exist for early stage breast cancer: (1) breast conserving surgery (BCS), (2) mastectomy with reconstruction (RECON), and (3) mastectomy alone. Current guidelines recommend that surgical treatment decisions should be based on patient preference if a patient is eligible for all 3. However, studies demonstrate persistent variation in the use of BCS and RECON. METHODS: Patients undergoing an operation for DCIS or stage I or II breast cancer at NCCN institutions between 2000 and 2006 were identified. Institutional procedure rates were determined. Spearman correlations measured the association between procedure types. Patient-level logistic regression models investigated predictors of procedure type and association with institutional supply of subspecialty care. RESULTS: Among 10,607 patients, 19% had mastectomy alone, 60% BCS, and 21% RECON. The institutional rate of BCS and RECON were strongly correlated (r = -0.80, P = 0.02). Institution was more important than all patient factors except age in predicting receipt of RECON or BCS. RECON was more likely for patients treated at an institution with a greater supply of reconstructive surgeons or where patients live further from radiation facilities. RECON was less likely at institutions with longer waiting times for surgery with reconstruction. CONCLUSIONS: Even within the NCCN, a consortium of multidisciplinary cancer centers, the use of BCS and mastectomy with reconstruction substantially varies by institution and correlates with the supply of subspecialty care.


Asunto(s)
Neoplasias de la Mama/cirugía , Carcinoma Ductal de Mama/cirugía , Carcinoma Intraductal no Infiltrante/cirugía , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Mamoplastia/estadística & datos numéricos , Mastectomía Segmentaria/estadística & datos numéricos , Mastectomía/estadística & datos numéricos , Grupo de Atención al Paciente/estadística & datos numéricos , Pautas de la Práctica en Medicina , Centros Médicos Académicos/provisión & distribución , Adulto , Factores de Edad , Anciano , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/patología , Neoplasias de la Mama/radioterapia , Carcinoma Ductal de Mama/epidemiología , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/radioterapia , Carcinoma Intraductal no Infiltrante/epidemiología , Carcinoma Intraductal no Infiltrante/patología , Carcinoma Intraductal no Infiltrante/radioterapia , Terapia Combinada , Femenino , Adhesión a Directriz/estadística & datos numéricos , Humanos , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Radioterapia Adyuvante/estadística & datos numéricos , Estudios Retrospectivos , Estados Unidos , Revisión de Utilización de Recursos/estadística & datos numéricos , Recursos Humanos
5.
Cancer Control ; 18(2): 96-103, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21451452

RESUMEN

BACKGROUND: Although most thyroid cancer patients have an excellent prognosis, 10% of low-risk cancers and 25% of high-risk cancers recur, with mortality rates in excess of 50% at 3 years for aggressive thyroid cancer. Traditional paradigms including surgery, I¹³¹ ablation, and TSH suppression do not offer additional therapeutic options for cancers that fail these interventions. Risk stratification and outcomes data are shifting the treatment paradigms to favor more individualized therapies based on risk, and new treatment targets have been identified with promise to treat more aggressive thyroid cancer. METHODS: The authors review the recent literature and published guidelines on thyroid cancer and summarize changing management paradigms and treatments of thyroid cancer. RESULTS: Outcomes data and risk stratification have promoted changes to traditional paradigms. Total/near-total thyroidectomy improves outcomes in both recurrence and mortality. Central compartment lymph node dissection facilitates nodal status determination and likely improves outcomes, while low-risk patients with small tumors are not likely to benefit from I¹³¹ remnant ablation. Early-phase studies have demonstrated significant improvement in progression-free survival with multikinase inhibitors targeting MAPK and angiogenic pathways. CONCLUSIONS: Risk stratification and outcomes data have modified treatment paradigms in thyroid cancer. Patients with progressive thyroid cancer that is no longer surgically resectable or iodine avid should be considered for treatment with multikinase inhibitors, preferably by enrollment in a therapeutic treatment trial.


Asunto(s)
Neoplasias de la Tiroides/terapia , Humanos , Radioisótopos de Yodo/uso terapéutico , Recurrencia Local de Neoplasia/terapia , Inhibidores de Proteínas Quinasas/uso terapéutico , Riesgo , Neoplasias de la Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/mortalidad , Ultrasonografía
6.
Cancer Control ; 18(2): 113-26, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21451454

RESUMEN

BACKGROUND: Adrenal lesions are commonly identified in patients with extra-adrenal cancer. When lesions are present, it is important to identify if the lesion is a metastasis of the primary cancer or a primary adrenal neoplasm. If primary, the adrenal lesion must be evaluated for hypersecretion and its malignant potential determined for appropriate treatment planning. METHODS: Recent literature was reviewed that focused on the normal investigation of adrenal lesions including radiographic imaging and hormonal evaluations as well as specific focused therapeutic options available for isolated metastatic adrenal lesions. RESULTS: This review presents a pathway approach in investigating these lesions and also discusses various potential treatment options. CONCLUSIONS: A proper investigative workup of an adrenal lesion in a cancer patient is critical for proper management. Isolated adrenal metastatic lesions in the cancer patient should be surgically removed when possible, but other options can be considered. In patients who do not have metastasis from extra-adrenal cancer, the decision for surgical resection is dependent on functionality of the tumor and it's potential for malignancy. Observation plays a key role in those tumors that are nonfunctioning and have a low risk of malignancy.


Asunto(s)
Neoplasias de las Glándulas Suprarrenales/secundario , Neoplasias de las Glándulas Suprarrenales/terapia , Glándulas Suprarrenales/patología , Neoplasias/patología , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Neoplasias de las Glándulas Suprarrenales/epidemiología , Ablación por Catéter , Humanos , Incidencia , Laparoscopía
8.
Ann Surg Oncol ; 18(1): 72-7, 2011 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-20585876

RESUMEN

BACKGROUND: Axillary ultrasound (AUS) with needle biopsy is used to detect metastasis in patients with invasive breast cancers. Our hypothesis is that preoperative AUS significantly reduces sentinel node biopsy (SLNB) use in patients with invasive breast tumors >2 cm upon clinical examination. METHODS: A single-institution database of patients with breast cancer and AUS was reviewed. Patients with incomplete records, clinical tumor <2 cm, or postoperative AUS were excluded. A control cohort of non-AUS patients with clinical T2 (cT2) or greater disease was identified. Clinicopathologic data were collected. Simple Kappa coefficient and chi-square statistical analyses were performed. RESULTS: AUS was performed in 153 patients vs. 370 controls. Of AUS patients, 112 (73.2%) had cT2 disease vs. 272 (73.5%) controls. Median AUS patient age was 53.7 (range, 22.8-85.8) years vs. 53.8 (range, 26.7-91.6) years; median pathologic tumor was 3.8 (range, 1.0-20.0) cm in AUS patients vs. 2.5 (range, 0.1-11.0) cm. Among AUS patients, 78% had needle biopsy; 85 of 120 (70.8%) were positive. Sixty-eight patients had SLNB: 33 after negative AUS and 35 after negative needle biopsy. Twenty-three SLNB (37.3%) were positive; 15 of 33 after negative AUS and 8 of 35 after a negative needle biopsy. Axillary dissection was performed in 102 of 153 vs. 225 of 370 controls. Sensitivity and specificity of AUS was 86.2% and 40.5%. Sensitivity of AUS plus needle biopsy was 89.3% with 100% specificity. Neoadjuvant chemotherapy was given to 49.7% of AUS patients. AUS reduced costs by more than $4,000 per patient. CONCLUSIONS: AUS reduces SLNB use and affects treatment in patients with cT2 or greater breast cancer. Routine AUS should be considered in this population.


Asunto(s)
Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/patología , Ultrasonografía Mamaria , Adulto , Anciano , Anciano de 80 o más Años , Axila , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Pronóstico , Sensibilidad y Especificidad , Biopsia del Ganglio Linfático Centinela , Adulto Joven
9.
Cancer Res ; 71(3): 1050-9, 2011 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-21169406

RESUMEN

Pathologic axillary lymph node (ALN) status is an important prognostic factor for staging breast cancer. Currently, status is determined by histopathology following surgical excision of sentinel lymph node(s), which is an invasive, time consuming, and costly procedure with potential morbidity to the patient. Here, we describe an imaging platform for noninvasive assessment of ALN status, eliminating the need for surgical examination of patients to rule out nodal involvement. A targeted imaging probe (MamAb-680) was developed by conjugation of a mammaglobin-A-specific monoclonal antibody to a near-infrared fluorescent dye. Using DNA and tissue microarray, mammaglobin-A was validated as a cell-surface target that is expressed in ALN-positive patient samples but is not expressed in normal lymph nodes. In vivo selectivity was determined by i.v. injection of MamAb-680 into mice with mammaglobin-A-positive and -negative mammary fat pad (MFP) tumors; and by peritumoral MFP injection of the targeted imaging probe in mice with spontaneous ALN metastases. Fluorescence imaging showed that probe was only retained in positive tumors and metastases. As few as 1,000 cells that endogenously express mammaglobin-A were detected in ALN, indicating high sensitivity of this method. Translation of this approach offers considerable potential as a noninvasive clinical strategy to stage breast cancer.


Asunto(s)
Anticuerpos Monoclonales/metabolismo , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Inmunoconjugados/metabolismo , Ganglios Linfáticos/patología , Proteínas de Neoplasias/biosíntesis , Uteroglobina/biosíntesis , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacocinética , Especificidad de Anticuerpos , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Diagnóstico por Imagen/métodos , Femenino , Colorantes Fluorescentes/metabolismo , Colorantes Fluorescentes/farmacocinética , Humanos , Inmunoconjugados/inmunología , Inmunoconjugados/farmacocinética , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Metástasis Linfática , Mamoglobina A , Ratones , Ratones Desnudos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Trasplante Heterólogo , Uteroglobina/genética , Uteroglobina/inmunología
10.
J Oncol Pract ; 7(5): 309-13, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22211128

RESUMEN

BACKGROUND: Axillary staging via sentinel node biopsy (SLNB) in patients with ductal carcinoma in situ with microinvasion (DCISM) is routinely performed but remains controversial with regard to the risk-benefit ratio. METHODS: Retrospective single-institution review of patients with diagnosis of DCISM (invasive tumor ≤ 0.1 cm). Age, clinicopathologic data, and follow-up were recorded. RESULTS: Of 90 patients, 33% were diagnosed by core needle biopsy (CNB), 37% by excisional biopsy, and 29% were upstaged from DCIS on CNB to DCISM at final operation. Three (10%) of 30 patients with DCISM on CNB were upstaged to invasive cancer on final pathology. Median age at diagnosis was 58.9 years (range: 30-89). Lumpectomy was performed in 45% of patients and mastectomy in 55%. Mean number of sentinel nodes was 2.59 (SE 0.17). Six (6.9%) of 87 patients with DCISM as final diagnosis had a positive SLNB (four lumpectomies, two mastectomies). There was no correlation with any clinicopathologic features, including palpable DCIS, DCIS grade/necrosis, or age at diagnosis. All six SLNB-positive patients had a complete axillary dissection; two had additional disease. Median follow-up time was 74.2 months (range: 2-169). In-breast recurrence was seen in three patients (5%), regardless of SLN status, DCIS grade, or necrosis. Two patients developed distant metastasis. Overall survival was 94.19% at 5 years for DCISM and 100% for DCISM with nodal disease. CONCLUSION: DCISM comprises 0.6% of breast cancer diagnoses at our institution. There is a low likelihood of nodal spread; however, a lack of identifiable clinicopathologic features associated with a positive SLNB limits selective SLNB use.

13.
J Am Coll Surg ; 209(6): 746-52; quiz 800-1, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19959044

RESUMEN

BACKGROUND: Bilateral/contralateral prophylactic mastectomy (PM) is offered to high-risk women to decrease their actual or perceived breast cancer risk. When an invasive occult cancer is identified, prevailing wisdom suggests that an axillary dissection be performed. This single-institution study aims to identify patients who may benefit from sentinel node biopsy (SLNB) at the time of prophylactic mastectomy. STUDY DESIGN: We performed a retrospective review of a prospective database of patients treated at our institution with bilateral/contralateral PM between 1995 and 2006. We examined patients' clinicopathologic characteristics in comparison with their incidence of occult cancer in the contralateral breast or axilla. RESULTS: There were 449 patients who underwent PM and SLNB. Twenty-eight underwent bilateral PM. Of the 28, no occult cancers were identified. Occult cancers were identified in 18 of 420 (4.3%) contralateral prophylactic specimens; they were invasive in 6 (1.4%). In cases of occult carcinoma, the primary established tumor was more likely to be of invasive lobular histology. Eight of 420 (2%) patients had a positive contralateral sentinel node, and within this subset of 8 patients the majority had locally advanced disease on the known tumor side. Other features associated with a positive contralateral sentinel node included the presence of lymphovascular involvement or skin or nipple involvement and grade 2 to 3 invasive primary established tumors. CONCLUSIONS: Overall, SLNB in patients undergoing bilateral PM or contralateral PM associated with early-stage disease is not indicated. But patients with locally advanced primary breast cancers have a significantly increased risk of occult cancer in the contralateral axilla, likely due to crossover metastasis; this select group of patients may benefit from SLNB at the time of surgery.


Asunto(s)
Neoplasias de la Mama/patología , Neoplasias de la Mama/prevención & control , Mastectomía , Biopsia del Ganglio Linfático Centinela , Neoplasias de la Mama/cirugía , Femenino , Humanos , Persona de Mediana Edad
14.
J Natl Compr Canc Netw ; 7(2): 122-92, 2009 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19200416
15.
Arch Biochem Biophys ; 482(1-2): 77-82, 2009 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19046938

RESUMEN

Endothelial integrity is dependent on intracellular adherens junctions formed by complexes of vascular endothelial (VE)-cadherin and catenins. We have previously demonstrated that exposing endothelial cells (EC) to breast cancer cell-conditioned media (CM) for 24h results in a reduction in VE-cadherin protein and mRNA levels. Herein, we examined the mechanism(s) involved in the downregulation of VE-cadherin by CM. Human dermal microvascular EC exposed to CM showed a downregulation in VE-cadherin promoter activity and upregulation of Twist, Slug, and Snail expression. Reporter gene analysis demonstrated a direct repression of the VE-cadherin promoter by Slug, Snail, and Twist expression plasmids. At least two E-box motifs appear to be involved in this regulatory process as shown by electrophoretic mobility shift assays. These results suggest that factors released by breast cancer cells are able to upregulate Twist, Slug, and Snail expression in EC, which in turn downregulate the activity of the VE-cadherin promoter.


Asunto(s)
Antígenos CD/genética , Cadherinas/genética , Proteínas Nucleares/genética , Regiones Promotoras Genéticas , Factores de Transcripción/genética , Proteína 1 Relacionada con Twist/genética , Neoplasias de la Mama , Carcinoma Hepatocelular , Línea Celular Tumoral , Medios de Cultivo Condicionados , Endotelio Vascular/fisiología , Células Epiteliales/fisiología , Femenino , Regulación Neoplásica de la Expresión Génica , Genes Reporteros , Humanos , Neoplasias Hepáticas , Plásmidos , ARN Mensajero/genética , Factores de Transcripción de la Familia Snail , Transcripción Genética , Transfección
16.
J Clin Oncol ; 26(34): 5553-60, 2008 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-18955448

RESUMEN

PURPOSE: To describe the frequency of chemotherapy use for hormone receptor (HR)-positive, lymph node (LN)-negative breast cancer from 1997 to 2004 at eight National Comprehensive Cancer Network institutions, to explore whether chemotherapy use varied over time and between institutions, and to identify factors associated with the decision to forego chemotherapy. PATIENTS AND METHODS: Among women younger than age 70 years with HR-positive, LN-negative breast cancer measuring more than 1 cm, we analyzed the frequency of chemotherapy use on a yearly basis. A multivariable logistic regression model assessed the relationship between receipt of chemotherapy and year of diagnosis, institution, tumor features, and patient characteristics. Interaction terms were added to the model, and stratified analyses were conducted to further explore the determinants of chemotherapy use. RESULTS: Fifty-five percent of 3,190 women received chemotherapy. Chemotherapy use was less common for patients with 1.1- to 2-cm tumors than for patients tumors greater 2 cm (47% v 87%, respectively; P < .01) and for women age 60 to 69 years versus women younger than age 50 years (24% v 76%, respectively; P < .01). On multivariable analysis, predictors independently associated with receiving chemotherapy included larger tumor size, higher grade, human epidermal growth factor receptor 2 overexpression, younger age, and institution (P < .01 for all). Institutions exhibited dramatically different rates of chemotherapy use (from 46% to 65%) and patterns of change in chemotherapy use over time (from a 79% relative increase to a 22% relative decrease). CONCLUSION: Although institutions seemed to agree that not all women with HR-positive, LN-negative breast cancer need chemotherapy, there did not seem to be consensus regarding which women should get chemotherapy. Only prospective randomized controlled trials will conclusively establish which subtypes of HR-positive, LN-negative breast cancer benefit from chemotherapy.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Receptores de Estrógenos/biosíntesis , Factores de Edad , Anciano , Estudios de Cohortes , Femenino , Humanos , Metástasis Linfática , Oncología Médica/métodos , Menopausia , Persona de Mediana Edad , Oportunidad Relativa , Receptores de Estrógenos/metabolismo , Análisis de Regresión , Resultado del Tratamiento
17.
Mol Cancer Ther ; 7(9): 2837-44, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18790764

RESUMEN

Agents that induce apoptosis in breast cancer cells have great potential to facilitate chemotherapeutic intervention and improve patient outcomes. In this study, the effects of injecting purified human chorionic gonadotropin (hCG) directly into human breast cancer xenografts grown in nude mice were examined. It was shown that intratumoral injection of purified hCG increased the apoptotic index in breast cancer xenografts. These results were supported by the findings that exposure of breast cancer cells to purified hCG decreased cell viability in five different breast cancer cell lines. In some of these cell lines, the effects of hCG in cell viability appear to correlate with activation/expression of the hCG/luteinizing hormone receptor. Preoperative apoptotic induction by factors such as purified hCG may improve local control or work synergistically with neoadjuvant chemotherapy to improve complete pathologic response of locally advanced breast cancer.


Asunto(s)
Apoptosis/efectos de los fármacos , Neoplasias de la Mama/patología , Gonadotropina Coriónica/aislamiento & purificación , Gonadotropina Coriónica/farmacología , 8-Bromo Monofosfato de Adenosina Cíclica/farmacología , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Humanos , Inmunohistoquímica , Antígeno Ki-67/metabolismo , Ratones , Ratones Desnudos , Proteínas de Neoplasias/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
18.
Ann Surg Oncol ; 14(10): 2971-8, 2007 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-17593333

RESUMEN

BACKGROUND: HER2 overexpression imparts a metastatic advantage in breast cancer. We have shown that HER2 signaling in breast cancer cells induces adjacent endothelial cell (EC) retraction, disrupting endothelial integrity. Because endothelial integrity is dependent on the adherens junctions, we postulated that the mechanism of tumor cell-induced EC retraction involves dissociation of catenin proteins from vascular endothelial (VE) cadherin. In this study, we report a loss of VE-cadherin in tumor-associated EC. We also tested for a change of catenin dissociation from VE-cadherin by manipulating HER2 signaling in tumor cells. METHODS: We tested confluent monolayers of human EC for downregulation of VE cadherin and dissociation of catenins from VE cadherin after exposure to breast cancer cells or conditioned media. Using immunoprecipitation, we quantitated the remaining complexed catenins to VE-cadherin in tumor-associated EC after different treatments to manipulate HER2 signaling. RESULTS: Treatment of EC with conditioned media from MCF-7 cells expressing HER2 induced a loss of VE-cadherin expression, and time-dependent dissociation of catenins from VE cadherin. Catenin dissociation from VE-cadherin was enhanced by Heregulin beta1 (P < .05) stimulation and decreased by trastuzumab (P < .05) blockade of HER2 signaling in cancer cells. An increase in EC phosphoSrc (Tyr 416) was seen by 8 hours. CONCLUSIONS: Our data suggest that HER2 induction of EC retraction involves both down-regulation of VE-cadherin and dissociation of catenins. HER2 signaling appears to regulate this potential metastatic mechanism. Further, Src phosphorylation suggests that this pathway may be involved in this mechanism.


Asunto(s)
Neoplasias de la Mama/genética , Cateninas/metabolismo , Transformación Celular Neoplásica/genética , Células Endoteliales/patología , Genes erbB-2/genética , Western Blotting , Neoplasias de la Mama/patología , Cadherinas/metabolismo , Línea Celular Tumoral , Transformación Celular Neoplásica/patología , Medios de Cultivo Condicionados , Regulación hacia Abajo/fisiología , Femenino , Regulación Neoplásica de la Expresión Génica/fisiología , Humanos , Técnicas In Vitro , Transducción de Señal/genética
20.
Cancer Res ; 67(4): 1487-93, 2007 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-17308086

RESUMEN

Abnormal activation of human epidermal growth factor receptor 2 (HER2; ErbB-2) in breast tumors results in increased metastasis and angiogenesis, as well as reduced survival. Here, we show that angiopoietin-2 (Ang-2) expression correlates with HER2 activity in human breast cancer cell lines. Inhibiting HER2 activity with anti-HER2 monoclonal antibody trastuzumab (Herceptin) or HER2 short interfering RNA in tumor cells down-regulates Ang-2 expression. Consistent with the important roles of AKT and mitogen-activated protein kinase in the HER2 signaling pathway, AKT and ERK mitogen-activated protein kinase (MAPK) kinase activity is necessary for Ang-2 up-regulation by HER2. Moreover, overexpression of HER2 protein up-regulates Ang-2 expression. Heregulin-beta1-induced Ang-2 up-regulation is abrogated when AKT and ERK kinase activity are blocked. Immunohistochemical analysis of HER2 and Ang-2 proteins in human breast carcinomas shows that Ang-2 expression in breast cancer correlates with HER2 expression. These studies provide evidence that the Ang-2 gene is regulated by HER2 activity in breast cancer, and propose an additional mechanism for HER2 contributing to tumor angiogenesis and metastasis.


Asunto(s)
Angiopoyetina 2/biosíntesis , Neoplasias de la Mama/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor ErbB-2/metabolismo , Angiopoyetina 2/genética , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/genética , Línea Celular Tumoral , Regulación hacia Abajo , Humanos , Inmunohistoquímica , Sistema de Señalización de MAP Quinasas , Fosfatidilinositol 3-Quinasas/metabolismo , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Receptor ErbB-2/biosíntesis , Receptor ErbB-2/genética , Transfección , Regulación hacia Arriba
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