Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The value of adjuvant endocrine therapy in saving lives of women with estrogen receptor-positive (ER(+)) early-stage breast cancer cannot be disputed. Tamoxifen has proven to be effective in improving relapse-free and overall survival in both pre- and postmenopausal women with ER(+) early-stage breast cancer. In the meta-analysis of the Early Breast Cancer Trialists' Collaborative Group, the proportional reduction in recurrence and mortality for 5 years of tamoxifen therapy was 50% and 28% respectively for patients with ER(+) tumors. These reductions in recurrence and mortality were similar in both lymph node-negative (N(-)) and lymph node-positive (N(+)) patients and translate to an absolute improvement in 10-year survival of approximately 11% in N(+) patients and 6% in N(-) patients. Current data suggest that about 5 years of tamoxifen therapy is the optimal duration of treatment. For women with ER(-)/progesterone receptor-negative (PR(-)) tumors, tamoxifen does not lower the risk of distant metastases or improve survival. In ER(+) patients, the addition of tamoxifen to chemotherapy further lowers the risk of recurrence by about 30% to 40% when compared to chemotherapy alone. In premenopausal women with ER(+) breast cancer, ovarian ablation has proven to be as effective as chemotherapy in improving both relapse-free and overall survival and the potential additive role of ovarian ablation to chemotherapy and/or tamoxifen is presently being explored in clinical trials. The combination of tamoxifen and ovarian ablation is currently being tested and may be superior to tamoxifen alone. In addition, newer, more effective, and less toxic aromatase inhibitors are also being evaluated in clinical trials in the adjuvant setting and have great promise. "Pure" antiestrogens or selective estrogen receptor down-regulators (SERDs) will be studied in adjuvant clinical trials in the near future. Recent data also suggest that molecular markers such as HER-2/neu may predict the response to endocrine therapy, and other predictive factors are currently being evaluated. Lastly, there is renewed interest in neoadjuvant endocrine therapy, a treatment option that may select those patients with early-stage breast cancer most likely to benefit from endocrine therapy.
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PMID:Role of adjuvant endocrine therapy in early-stage breast cancer. 1149 25

The effects of tamoxifen, an antiestrogen, on the inhibition of protein tyrosine phosphorylation in neu/c-erbB-2 receptor, DNA synthesis and proliferation were evaluated using the malignant glioma cell lines U25 IMG and T98G which overexpressing neu/c-erbB-2. Pretreatment of two cell lines with tamoxifen resulted in a dose dependent inhibition of tyrosine phosphorylation as well as DNA synthesis and cell growth in two cell lines correlatively. The results support the hypothesis that activated protein tyrosine kinase receptors are involved in the proliferation of glioma cells. Tamoxifen may be useful in the treatment of malignant glioma.
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PMID:Tamoxifen interacts with NEU/C-ERBB-2 receptor and inhibits growth of human malignant glioma cell lines. 1172 74

HER2 overexpression has been associated with anti-estrogen resistance in human breast cancer, and it has been suggested that the combined treatment of an anti-HER2 antibody plus tamoxifen has enhanced anti-cancer efficacy in breast cancer. The detailed anti-proliferative interactions between trastuzumab and tamoxifen were analyzed with the isobologram and Chou and Talalay methods, which assess the presence of synergy, addition or antagonism. We used the breast cancer cell lines that are estrogen receptor (ER)-positive and HER2-positive. We also analyzed the molecular changes on the HER2 and (ER) signaling pathways that are induced by trastuzumab plus tamoxifen. In terms of cancer cell proliferation, the simultaneous combination of trastuzumab and tamoxifen on BT-474 cells was more growth inhibitory (44%) than the treatment with trastuzumab (24%) or tamoxifen (31%) alone. Isobologram analysis of simultaneous trastuzumab plus tamoxifen exposure showed, however, that there were antagonistic interactions at an effect level of 30% (IC30). Using Chou and Talalay analysis we also observed antagonistic interactions at lower levels of cell kill, although there were additive effects at highest levels of cell kill. Trastuzumab followed by tamoxifen showed antagonism at all effects levels. Tamoxifen followed by trastuzumab showed antagonism at lower levels of cell kill, and additivity at higher levels of cell kill. Similar interactions were observed using T47D cells. The molecular effects of the combined treatment with trastuzumab plus tamoxifen on the levels of HER2 and ER signaling showed that, with respect to HER2 protein levels, trastuzumab downregulated HER2 by 27%, tamoxifen upregulated HER2 by 40%, and the combination of trastuzumab plus tamoxifen did not induce changes in HER2 respect to control. With respect to HER2 mRNA, trastuzumab upregulated HER2 mRNA to 367%, tamoxifen to 166%, and the combination to 401%. With respect to HER2 phosphorylation, trastuzumab upregulated HER2 phosphorylation to 352%, tamoxifen to 202% and the combination to 633%. Epidermal growth factor receptor levels were not changed by trastuzumab or tamoxifen alone, and were upregulated to 138% by the combination. The protein levels and activity of extracellular recptor kinase were not modified by trastuzumab, tamoxifen or the combination. Finally, estrogen receptor protein and mRNA levels were downregulated to about 50% by trastuzumab, tamoxifen or the combination. Taken together, our results show that in ER-positive breast cancer cells overexpressing HER2, trastuzumab plus tamoxifen have antagonistic interactions when used in combination, and that this antagonism may be related with an increase in HER2 signaling pathways that occurs when tamoxifen is added to trastuzumab.
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PMID:Trastuzumab plus tamoxifen: anti-proliferative and molecular interactions in breast carcinoma. 1531 65

A novel in vivo model of tamoxifen-stimulated endometrial cancer was developed and the role of HER-2/neu investigated by using trastuzumab. Tamoxifen-stimulated tumors (ECC-1TAM) were growth stimulated by 17beta-estradiol (E2), tamoxifen, or raloxifene. Trastuzumab inhibited growth of E2-stimulated ECC-1E2 tumors by 50% and tamoxifen-stimulated ECC-1TAM tumors by 100%. ECC-1 tumors expressed functional estrogen receptor alpha (ER alpha) as measured by induction of pS2 and c-myc mRNAs. E2 induced pS2 and c-myc mRNAs up to 40-fold in ECC-1E2 and ECC-1TAM. Tamoxifen induced pS2 and c-myc mRNAs up to 5-fold in ECC-1E2 tumors and up to 10-fold in ECC-TAM tumors. Trastuzumab blocked E2-induced pS2 mRNA (P < 0.01) in ECC-1E2 by 50% and tamoxifen-induced c-myc mRNA (P < 0.1) in ECC-1TAM tumors by 70%. Trastuzumab decreased phosphorylated and total HER-2/neu protein in ECC-1E2 and ECC-1TAM tumors. However, only phospho-ERK-1/2 and not phospho-Akt protein was decreased by trastuzumab in tamoxifen-treated ECC-1TAM tumors. The insulin-like growth factor (IGF-I) signaling pathway also activates extracellular signal-related kinase (ERK)-1/2 and could block the efficacy of trastuzumab in ECC-1E2 tumors. The results showed that IGF-I, IGF-IR mRNAs, and phospho-insulin receptor substrate-1 (IRS-1) protein were decreased in ECC-1TAM compared with ECC-1E2 tumors. The results show that trastuzumab is an effective therapy for both E2-stimulated and tamoxifen-stimulated endometrial cancer. The data suggest estrogenic activities of E2 and tamoxifen at ER alpha-regulated pS2 and c-myc genes are in part mediated by HER-2/neu. However, trastuzumab is a better growth inhibitor of ECC-1TAM tumors where there is diminished IGF-I signaling allowing for complete blockade of the downstream phospho-ERK-1/2 signal.
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PMID:Trastuzumab therapy for tamoxifen-stimulated endometrial cancer. 1616 31

Tamoxifen remains a frontline treatment for hormone-responsive breast cancer despite its use being associated with a 2-7-fold elevated risk of developing endometrial carcinoma. Several groups have investigated whether tamoxifen induces DNA-damaging (genotoxic) versus non-genotoxic mechanisms. Some studies point to the presence of tamoxifen-DNA adducts while others suggest otherwise. In many of these studies, the histological sub-type has not been considered; as type 1 carcinomas are associated with PTEN and KRAS2 mutations whereas type 2 carcinomas exhibit TP53 and ERBB-2 mutations, the absence of this information makes comparisons between such independent investigations difficult. An examination of the sub-types of endometrial carcinoma points to histological and mechanistic distinctions between sporadic and tamoxifen-associated disease; this could suggest differing aetiologies. On this basis, we propose a dual mechanism of action highlighted by the different patterns of endometrial carcinoma sub-types. Tamoxifen may initially be pro-oestrogenic in the endometrium giving rise to elevated type 1 endometrioid carcinoma occurrence whereas after long-term use, there is an increase of type 2 disease or malignant mixed mullerian tumours associated with a hormone-independent mechanism of action. Despite these associated risk factors, and the introduction of new selective oestrogen receptor modulators (SERMs), we suggest that the organ-specific pleiotrophic effects of tamoxifen mean that this effective therapeutic agent for breast cancer will continue to have significant usage. The focus of future research should concentrate on the different aetiologies of tamoxifen-associated endometrial carcinomas while efforts continue to develop future SERMs.
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PMID:Tamoxifen: important considerations of a multi-functional compound with organ-specific properties. 1717 95

Breast cancer is the most common cancer and the second leading cause of cancer death in American women. It was the second most common cancer in the world in 2002, with more than 1 million new cases. Despite advances in early detection and the understanding of the molecular bases of breast cancer biology, about 30% of patients with early-stage breast cancer have recurrent disease. To offer more effective and less toxic treatment, selecting therapies requires considering the patient and the clinical and molecular characteristics of the tumor. Systemic treatment of breast cancer includes cytotoxic, hormonal, and immunotherapeutic agents. These medications are used in the adjuvant, neoadjuvant, and metastatic settings. In general, systemic agents are active at the beginning of therapy in 90% of primary breast cancers and 50% of metastases. However, after a variable period of time, progression occurs. At that point, resistance to therapy is not only common but expected. Herein we review general mechanisms of drug resistance, including multidrug resistance by P-glycoprotein and the multidrug resistance protein family in association with specific agents and their metabolism, emergence of refractory tumors associated with multiple resistance mechanisms, and resistance factors unique to host-tumor-drug interactions. Important anticancer agents specific to breast cancer are described. Breast cancer is the most common type of cancer and the second leading cause of cancer death in American women. In 2002, 209,995 new cases of breast cancer were registered, and 42,913 patients died of it. In 5 years, the annual prevalence of breast cancer will reach 968,731 cases in the United States. World wide, the problem is just as significant, as breast cancer is the most frequent cancer after nonmelanoma skin cancer, with more than 1 million new cases in 2002 and an expected annual prevalence of more than 4.4 million in 5 years. Breast cancer treatment currently requires the joint efforts of a multidisciplinary team. The alternatives for treatment are constantly expanding. With the use of new effective chemotherapy, hormone therapy, and biological agents and with information regarding more effective ways to integrate systemic therapy, surgery, and radiation therapy, elaborating an appropriate treatment plan is becoming more complex. Developing such a plan should be based on knowledge of the benefits and potential acute and late toxic effects of each of the therapy regimens. Despite advances in early detection and understanding of the molecular bases of breast cancer biology, approximately 30% of all patients with early-stage breast cancer have recurrent disease, which is metastatic in most cases. The rates of local and systemic recurrence vary within different series, but in general, distant recurrences are dominant, strengthening the hypothesis that breast cancer is a systemic disease from presentation. On the other hand, local recurrence may signal a posterior systemic relapse in a considerable number of patients within 2 to 5 years after completion of treatment. To offer better treatment with increased efficacy and low toxicity, selecting therapies based on the patient and the clinical and molecular characteristics of the tumor is necessary. Consideration of these factors should be incorporated in clinical practice after appropriate validation studies are performed to avoid confounding results, making them true prognostic and predictive factors. A prognostic factor is a measurable clinical or biological characteristic associated with a disease-free or overall survival period in the absence of adjuvant therapy, whereas a predictive factor is any measurable characteristic associated with a response or lack of a response to a specific treatment. The main prognostic factors associated with breast cancer are the number of lymph nodes involved, tumor size, histological grade, and hormone receptor status, the first two of which are the basis for the AJCC staging system. The sixth edition of the American Joint Committee on Cancer staging system allows better prediction of prognosis by stage. However, after determining the stage, histological grade, and hormone receptor status, the tumor can behave in an unexpected manner, and the prognosis can vary. Other prognostic and predictive factors have been studied in an effort to explain this phenomenon, some of which are more relevant than others: HER-2/neu gene amplification and protein expression, expression of other members of the epithelial growth factor receptor family, S phase fraction, DNA ploidy, p53 gene mutations, cyclin E, p27 dysregulation, the presence of tumor cells in the circulation or bone marrow, and perineural and lymphovascular space invasion. Systemic treatment of breast cancer includes the use of cytotoxic, hormonal, and immunotherapeutic agents. All of these agents are used in the adjuvant, neoadjuvant, and metastatic setting. Adjuvant systemic therapy is used in patients after they undergo primary surgical resection of their breast tumor and axillary nodes and who have a significant risk of systemic recurrence. Multiple studies have demonstrated that adjuvant therapy for early-stage breast cancer produces a 23% or greater improvement in disease-free survival and a 15% or greater increase in overall survival rates. Recommendations for the use of adjuvant therapy are based on the individual patient's risk and the balance between absolute benefit and toxicity. Anthracycline-based regimens are preferred, and the addition of taxanes increases the survival rate in patients with lymph node-positive disease. Adjuvant hormone therapy accounts for almost two thirds of the benefit of adjuvant therapy overall in patients with hormone-receptor-positive breast cancer. Tamoxifen is considered the standard of care in premenopausal patients. In comparison, the aromatase inhibitor anastrozole has been proven to be superior to tamoxifen in postmenopausal patients with early-stage breast cancer. The adjuvant use of monoclonal antibodies and targeted therapies other than hormone therapy is being studied. Interestingly, some patients have an early recurrence even though they have a tumor with good prognostic features and at a favorable stage. These recurrences have been explained by the existence of certain cellular characteristics at the molecular level that make the tumor cells resistant to therapy. Selection of resistant cell clones of micrometastatic disease has also been proposed as an explanation for these events. Neoadjuvant systemic therapy, which is the standard of care for patients with locally advanced and inflammatory breast cancer, is becoming more popular. It reduces the tumor volume, thus increasing the possibility of breast conservation, and at the same time allows identification of in vivo tumor sensitivity to different agents. The pathological response to neoadj uvant systemic therapy in the breast and lymph nodes correlates with patient survival. Use of this treatment modality produces survival rates identical to those obtained with the standard adjuvant approach. The rates of pathological complete response (pCR) to neoadjuvant systemic therapy vary according to the regimen used, ranging from 6% to 15% with anthracycline-based regimens to almost 30% with the addition of a noncross-resistant agent such as a taxane. In one study, the addition of neoadjuvant trastuzumab in patients with HER-2-positive breast tumors increased the pCR rate to 65%. Primary hormone therapy has also been used in the neoadjuvant systemic setting. Although the pCR rates with this therapy are low, it significantly increases breast conservation. Currently, neoadjuvant systemic therapy is an important tool in not only assessing tumor response to an agent but also studying the mechanisms of action of the agent and its effects at the cellular level. However, no tumor response is observed in some cases despite the use of appropriate therapy. The tumor continues growing during treatment in such cases, a phenomenon called primary resistance to therapy. The use of palliative systemic therapy for metastatic breast cancer is challenging. Five percent of newly diagnosed cases of breast cancer are metastatic, and 30% of treated patients have a systemic recurrence. Once metastatic disease develops, the possibility of a cure is very limited or practically nonexistent. In this heterogeneous group of patients, the 5-year survival rate is 20%, and the median survival duration varies from 12 to 24 months. In this setting, breast cancer has multiple clinical presentations, and the therapy for it should be chosen according to the patient's tumor characteristics, previous treatment, and performance status with the goal of improving survival without compromising quality of life. Treatment resistance is most commonly seen in such patients. They initially may have a response to different agents, but the responses are not sustained, and, in general, the rates of response to subsequent agents are lower. Table 1 summarizes metastatic breast cancer response rates to single-agent systemic therapy.
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PMID:Overview of resistance to systemic therapy in patients with breast cancer. 1799 29

The possible interference of tamoxifen with anti-tumor vaccines was studied in a translational view of combined preventive approaches. Tamoxifen treatment of HER-2/neu transgenic mice combined to anti-HER-2/neu cell vaccine did not hamper the efficacy of cancer immunoprevention, and caused a significantly increased production of interferon-gamma. These data suggest that tamoxifen could even have a positive impact on the efficacy of cancer immunoprevention.
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PMID:Tamoxifen combined to anti-HER-2/neu cell vaccine does not hamper cancer immunopreventive efficacy. 1942 31

Tamoxifen and alpha-interferon have interesting and complementary biologic effects which may be relevant for breast cancer growth and regression. The hormone responsive cell line MCF-7 was used as a model to study the biologic effects of sequential administration of these two agents. Interferon had a significant antiproliferative effect and increased ER and TGF-beta expression. The combination had at least additive antiproliferative effects as well as effects on expression of ER, TGF-beta, c-erbB-2, P24 and Ki67. alpha-IFN modulates TMX induced biologic effects and the sequential administration of alpha-IFN and TMX may lead to potentially important modulation of biologic endpoints. Further studies are appropriate.
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PMID:Sequential alpha-interferon and tamoxifen. 2153 16


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