RESUMEN
BACKGROUND: Cell culture studies have disclosed that the mitotic Aurora kinase A is causally involved in both tamoxifen and aromatase inhibitor resistant cell growth and thus may be a potential new marker for endocrine resistance in the clinical setting. MATERIAL AND METHODS: Archival tumor tissue was available from 1323 Danish patients with estrogen receptor (ER) positive primary breast cancer, who participated in the Breast International Group (BIG) 1-98 trial, comparing treatment with tamoxifen and letrozole and both in a sequence. The expression of Aurora A was determined by immunohistochemistry in 980 tumors and semi quantitively scored into three groups; negative/weak, moderate and high. The Aurora A expression levels were compared to other clinico-pathological parameters and outcome, defined as disease-free survival (DFS) and overall survival (OS). RESULTS: High expression of Aurora A was found in 26.9% of patients and moderate in 57.0%. High expression was significantly associated with high malignancy grade and HER2 amplification. High Aurora A expression was significantly more frequent in ductal compared to lobular carcinomas. We found no significant association between Aurora A expression and DFS or OS and no evidence of interaction between Aurora A expression and benefits from tamoxifen versus letrozole. CONCLUSIONS: Aurora A expression in breast tumors was associated with high malignancy grade III and with HER2 amplification. A trend as a prognostic factor for OS was found in patients with high Aurora A expression. No predictive property was observed in this study with early breast cancer.
Asunto(s)
Aurora Quinasa A/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Resistencia a Antineoplásicos , Receptores de Estrógenos/metabolismo , Antineoplásicos Hormonales/uso terapéutico , Inhibidores de la Aromatasa/uso terapéutico , Biomarcadores/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/mortalidad , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/terapia , Carcinoma Lobular/metabolismo , Carcinoma Lobular/mortalidad , Carcinoma Lobular/patología , Carcinoma Lobular/terapia , Dinamarca/epidemiología , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Letrozol , Nitrilos/uso terapéutico , Pronóstico , Receptor ErbB-2/metabolismo , Tamoxifeno/uso terapéutico , Triazoles/uso terapéuticoRESUMEN
In this study, T47D cell lines resistant to the antiestrogen fulvestrant were established and analyzed to explore, whether a switch to HER signaling, as seen in fulvestrant resistant MCF-7 cell lines, is a general resistance mechanism. We find that parental T47D cells depend on ER and HER signaling for growth. Fulvestrant resistant T47D cells have lost ER expression and, although HER2 was over expressed, growth was only partially driven by HER receptors. Instead c-Src was important for resistant growth. Thus, the T47D and MCF-7 model system unravel different resistance mechanisms which may be important for fulvestrant resistant breast cancer patients.
