Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dysregulation of ErbB receptor tyrosine kinases is thought to promote mammary tumor progression by stimulating tumor cell growth and invasion. Overexpression and aberrant activation of ErbB2/HER2 confer aggressive and malignant characteristics to breast cancer cells, and patients displaying ErbB2-amplified breast cancer face a worsened prognosis. Recent studies have established that ErbB2 and ErbB3 are commonly co-overexpressed in breast tumor cell lines and in patient samples. ErbB2 heterodimerizes with and activates the ErbB3 receptor, and the two receptors synergize in promoting growth factor-induced cell proliferation, transformation, and invasiveness. Our previous studies have shown that the neuregulin receptor degradation protein-1 (Nrdp1) E3 ubiquitin ligase specifically suppresses cellular ErbB3 levels by marking the receptor for proteolytic degradation. Here, we show that overexpression of Nrdp1 in human breast cancer cells results in the suppression of ErbB3 levels, accompanied by the inhibition of cell growth and motility and the attenuation of signal transduction pathways. In contrast, either Nrdp1 knockdown or the overexpression of a dominant-negative form enhances ErbB3 levels and cellular proliferation. Additionally, Nrdp1 expression levels inversely correlate with ErbB3 levels in primary human breast cancer tissue and in a mouse model of ErbB2 mammary tumorigenesis. Our observations suggest that Nrdp1-mediated ErbB3 degradation suppresses cellular growth and motility, and that Nrdp1 loss in breast tumors may promote tumor progression by augmenting ErbB2/ErbB3 signaling.
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PMID:Loss of Nrdp1 enhances ErbB2/ErbB3-dependent breast tumor cell growth. 1714 73

Pertuzumab (Omnitarg) is a novel antibody against HER-2, domain II. HER-2 is a tyrosine kinase receptor that is overexpressed in several carcinomas, especially breast cancer. Pertuzumab, labeled with the low-energy beta emitter (177)Lu, might be a candidate for targeted radiotherapy of disseminated HER-2-positive micrometastases. The radiolabeled antibody [(177)Lu]pertuzumab showed favorable targeting properties in BALB/c (nu/nu) mice with HER-2-overexpressing xenografts. The absorbed dose in tumors was more than five times higher than the absorbed dose in blood and more than seven times the absorbed dose in any other normal organ. Experimental therapy showed that [(177)Lu]pertuzumab delayed tumor progression compared with controls (no treatment, P < 0.0001; nonlabeled pertuzumab antibody, P < 0.0001; and (177)Lu-labeled irrelevant antibody, P < 0.01). No adverse side effects of the treatment could be detected. Thus, the experimental results support the planning of clinical studies applying [(177)Lu]pertuzumab for therapy.
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PMID:[177Lu]pertuzumab: experimental therapy of HER-2-expressing xenografts. 1721 Jul 14

The epidermal growth factor receptor (EGFR) is implicated in cancer progression and development and, being overexpressed in a variety of human malignancies, is an attractive target for selective anticancer therapy. EGFR tyrosine kinase inhibitors (TKIs) have been demonstrated to produce dramatic and durable responses in a fraction of non-small cell lung cancer patients. During the last few years, clinical and biological predictors for TKI sensitivity have been identified. Among clinical features, never-smoking history seemed the most critical factor, probably because of the different spectrum of molecular abnormalities associated with cigarette-smoking exposure. Among biological predictors, several studies indicate that EGFR mutations and increased EGFR gene copy number are implicated in response to TKI therapy, with conflicting results in survival. Mutations in the EGFR gene as well as in K-ras and HER2 genes seemed to impair TKI effects, leading to TKI resistance. Because most available data come from retrospective studies, there is an urgent need to validate these results in prospective trials. Several studies have been recently completed, and these data could indicate how to properly select patients who are candidates for TKI therapy.
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PMID:Understanding the new genetics of responsiveness to epidermal growth factor receptor tyrosine kinase inhibitors. 1729 17

HER2/neu is overexpressed in about 20% of invasive breast carcinomas. Numerous studies have shown that there is high level of concordance between the HER2/neu status of the primary breast cancer and the metastases of a given patient. Recently, changes in HER2/neu status with tumor progression have been reported, suggesting the possibility of an emerging different tumor clone. Little is known about intratumoral heterogeneity with regard to HER2/neu oncoprotein overexpression. We identified nine cases of invasive ductal carcinoma that showed intratumoral variation in HER2/neu oncoprotein expression by immunohistochemistry. This was confirmed by the intratumoral variation in the amplification status of the HER2/neu gene by fluorescence in situ hybridization and by chromogenic in situ hybridization. The results of this study suggest that some cases of primary breast carcinoma are heterogeneous in regard to HER2/neu gene amplification or protein overexpression. Heterogeneity of HER2/neu status in a tumor may be a rare event or underestimated. This phenomenon should be examined as it may contribute to a better understanding of the variation in therapeutic responses and the conflicting data in studies about the prognostic and predictive role of HER2/neu status in subsets of breast cancer patients.
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PMID:Intratumoral heterogeneity of HER2/neu in breast cancer--a rare event. 1731 52

HER-2/neu status of the primary breast cancer (PBC) is determined by immunohistochemistry and fluorescent in situ hybridization. Because of a variety of technical factors, however, the PBC may not accurately reflect the metastatic tumor in terms of HER-2/neu status. Recently published guidelines recommend that tumors be defined as HER-2/neu positive if 30% or more of the cells are 3+. Circulating levels of the HER-2 extracellular domain can be measured in serum using a test cleared by the US Food and Drug Administration, and increased serum HER-2/neu levels to above 15 ng/ml can reflect tumor progression. Studies comparing tissue HER-2/neu status of the PBC and HER-2/neu levels above 15 ng/ml in metastatic breast cancer patients are also reviewed.
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PMID:HER-2/neu diagnostics in breast cancer. 1756 91

Biologic agents represent an already proven addition in the armamentarium of anticancer weapons. Anti-HER2 therapy was the first to demonstrate survival benefit by associating a targeted agent to cytotoxic chemotherapy. Four major adjuvant trials--Herceptin Adjuvant (HERA), National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31, North Central Cancer Treatment Group (NCCTG) N9831, and Breast Cancer International Research Group (BCIRG) 006--including more than 13,000 women with HER-2-positive early breast cancer, have investigated different adjuvant treatment approaches with trastuzumab. These trials have shown that trastuzumab reduces the 3-year risk of recurrence by about half in this patient population. Accurate testing for HER2 amplification/overexpression is essential before treatment initiation. Patients progressing while on combined chemotherapy and trastuzumab may still benefit from continuation of trastuzumab with other agents; evidence also supports the use of the capecitabine/lapatinib combination in this setting, which improves response and time to further tumor progression. Antiangiogenic therapy with bevacizumab in association with weekly paclitaxel improves disease-free survival for metastatic breast cancer patients. Future studies will provide much needed data on predicting response to biologic therapies, revealing the mechanisms of resistance to such therapies and maximizing the patient's benefit.
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PMID:Integrating biological agents into systemic therapy of breast cancer: trastuzumab, lapatinib, bevacizumab. 1793 69

While the acquisition of invasiveness is a critical step in early stage breast carcinomas (DCIS), no established molecular markers reliably identify tumor progression. The metastasis gene osteopontin is subject to alternative splicing, which yields 3 messages, osteopontin-a, osteopontin-b and osteopontin-c. Osteopontin-c is selectively expressed in invasive, but not in noninvasive, breast tumor cell lines, and it effectively supports anchorage independence. We evaluated osteopontin-c as a biomarker. The RNA message for osteopontin-c was present in 16 of 20 breast cancers (80%), but was undetectable in 22 normal specimens obtained from reduction mammoplasty. In contrast, osteopontin-a RNA was expressed at various levels in all 20 breast cancers, 11 tumor-surrounding tissues and 21 normal samples. The splice variant osteopontin-b was present at barely detectable levels in 18 of 20 cancers and in 6 of 22 normal breasts. By immunohistochemistry, 66 of 69 normal breasts were negative, while 3 showed low level staining. Among the breast cancers, 43 of 56 cores (77%) stained positive for osteopontin-c. When correlated with tumor grade, the staining for osteopontin-c increased from grade 1 to grade 3. In a total of 178 breast specimens analyzed, osteopontin-c was present in 78% of cancers, 36% of surrounding tissues and 0% of normal tissues. Furthermore, osteopontin-c detects a higher fraction of breast cancers than estrogen receptor (ER), progesterone receptor or HER2. In conjunction, osteopontin-c, ER and HER2 reliably predict grade 2-3 breast cancer. Hence, osteopontin-c is a diagnostic and prognostic marker that may have value in a diagnostic panel together with conventional breast cancer markers.
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PMID:Osteopontin-c is a selective marker of breast cancer. 1830 53

LFM-A13 (alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)propenamide) has recently been identified as an inhibitor of Polo-like kinases (Plk). LFM-A13 does not inhibit other serine/threonine kinases including CDK, CHK, RAF, DAPK, IKK, IRAK, JNK, MAPK, PKC and SAPK. LFM-A13-treated human cancer cells develop abnormal mitotic spindles and G(2)/M-arrest during cell cycle progression. LFM-A13 was not toxic to rodents or dogs at daily dose levels as high as 100 mg/kg. Notably, at a low dose level of 10 mg/kg, which does not result in delayed tumor progression in the MMTV/neu transgenic mouse model of HER2 positive breast cancer, LFM-A13 markedly enhanced the anti-cancer activity of the mitotic spindle poison paclitaxel. These results indicate that LFM-A13 may be useful in the treatment of cancer patients.
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PMID:Chemosensitizing anti-cancer activity of LFM-A13, a leflunomide metabolite analog targeting polo-like kinases. 1807 37

It is widely accepted that metastasis is a late event in cancer progression. Here, however, we show that tumor cells can disseminate systemically from earliest epithelial alterations in HER-2 and PyMT transgenic mice and from ductal carcinoma in situ in women. Wild-type mice transplanted with single premalignant HER-2 transgenic glands displayed disseminated tumor cells and micrometastasis in bone marrow and lungs. The number of disseminated cancer cells and their karyotypic abnormalities were similar for small and large tumors in patients and mouse models. When activated by bone marrow transplantation into wild-type recipients, 80 early-disseminated cancer cells sufficed to induce lethal carcinosis. Therefore, release from dormancy of early-disseminated cancer cells may frequently account for metachronous metastasis.
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PMID:Systemic spread is an early step in breast cancer. 1816 40

Chemotherapy treatment choices for metastatic breast cancer (MBC) have become increasingly complex as therapeutic options multiply. In addition, the more frequent use of adjuvant chemotherapy coupled with the introduction of new standard adjuvant therapies has made these choices more difficult. Another issue that remains unsettled is whether to employ combination therapy or to use each agent singly until its value is exhausted. The results of recent studies investigating this issue have revealed higher response rates, time to tumor progression and, in some cases, improved overall survival with doublet therapy. However, there was no planned crossover in these trials and, as such, the absolute benefits of doublet therapy remain undetermined. The future of therapy for MBC appears to be combining effective single-agent chemotherapy with novel biologic agents. For example, compared with paclitaxel alone, therapy comprising paclitaxel plus bevacizumab produced a doubling of response rate and progression-free survival. However, similar data are required for both the first- and the second-line setting, and for other chemotherapy agents, for example, docetaxel and navelbine. Trastuzumab is the treatment of choice for patients with HER2-positive tumors. Its use in combination with chemotherapy, particularly the taxanes, is well established. However, much remains to be learned about biologic agents; for example, trials need to establish whether these therapies should be continued at the time of progression or whether other treatments should be given in their place. A recent study in patients whose disease had progressed after trastuzumab and chemotherapy and who were subsequently given lapatinib, has reported promising outcomes for this agent. When presented with the many options that are now available for the treatment of MBC, we must keep in mind the primary goal of such treatment: palliation of disease with minimal toxicity. Furthermore, a concurrent requirement for prolongation of survival is now commonplace. However, it is clear that there is currently no "gold standard" treatment for MBC, although the future of therapy appears to be the combination of effective single agents with novel biologic therapies.
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PMID:Considerations in treatment choice for metastatic breast cancer. 1822 92


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