Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278488 (metastatic breast cancer)
 7,812 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IGF-1 and 2 are thought to be important growth factors for breast cancer. However, gene expression of IGFs or IGF receptors in breast cancer tissues, and especially in metastatic breast cancer cells, is not well known. Expression of mRNA encoding for IGF-1, IGF-2, IGF-receptor 1 and 2, IGF binding proteins- 1 to -6, insulin receptor and insulin was determined in the NIH MCF-7 breast cancer cell line, in specimens from breast cancer tissues, and in 6 primary breast cancer cell cultures obtained from metastatic breast cancer, using rT-PCR technique. Specific mRNA sequences encoding for IGF-receptor 1 and 2, IGFBP-2, -4 and insulin receptor were identified in all cell cultures and most of the tissue specimens. Though in most of the tissues additional expression of IGF-1 and IGF-2 was detected, there was no mRNA encoding for these proteins in MCF-7 cell cultures as well as in the primary cell cultures of metastatic breast cancers. In none of our specimens mRNA encoding for IGFBP-1, -3, -5, -6 and insulin was detectable. IGF-receptor expression in cancer tissues and metastatic breast cancer cells supports the hypothesis that IGFs increase tumor cell proliferation in vivo. Expression of IGF-1 and IGF-2 in tumor tissues but not in cancer cell cultures indicates an IGF expression located predominantly in stromal parts of cancer tissues.
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PMID:mRNA expression of components of the insulin-like growth factor system in breast cancer cell lines, tissues, and metastatic breast cancer cells. 961 87

Unsustained enzyme inhibition is a barrier to targeted therapy for cancer. Here, resistance to a class I PI3K inhibitor in a model of metastatic breast cancer driven by PI3K and MYC was associated with feedback activation of tyrosine kinase receptors (RTKs), AKT, mTOR, and MYC. Inhibitors of bromodomain and extra terminal domain (BET) proteins also failed to affect tumor growth. Interestingly, BET inhibitors lowered PI3K signaling and dissociated BRD4 from chromatin at regulatory regions of insulin receptor and EGFR family RTKs to reduce their expression. Combined PI3K and BET inhibition induced cell death, tumor regression, and clamped inhibition of PI3K signaling in a broad range of tumor cell lines to provide a strategy to overcome resistance to kinase inhibitor therapy.
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PMID:Kinase and BET Inhibitors Together Clamp Inhibition of PI3K Signaling and Overcome Resistance to Therapy. 2605 79

Numerous solid tumors overexpress or have excessively activated insulin-like growth factor receptor-1 (IGF-1R). We summarize preclinical studies and the first-in-human study of KW-2450, an oral tyrosine kinase inhibitor with IGF-1R and insulin receptor (IR) inhibitory activity. Preclinical activity of KW-2450 was evaluated in various in vitro and in vivo models. It was then evaluated in a phase I clinical trial in 13 patients with advanced solid tumors (NCT00921336). In vitro, KW-2450 inhibited human IGF-1R and IR kinases (IC50 7.39 and 5.64 nmol/L, respectively) and the growth of various human malignant cell lines. KW-2450 40 mg/kg showed modest growth inhibitory activity and inhibited IGF-1-induced signal transduction in the murine HT-29/GFP colon carcinoma xenograft model. The maximum tolerated dose of KW-2450 was 37.5 mg once daily continuously; dose-limiting toxicity occurred in two of six patients at 50 mg/day (both grade 3 hyperglycemia) and in one of seven patients at 37.5 mg/day (grade 3 rash). Four of 10 evaluable patients showed stable disease. Single-agent KW-2450 was associated with modest antitumor activity in heavily pretreated patients with solid tumors and is being further investigated in combination therapy with lapatinib/letrozole in patients with human epidermal growth factor receptor 2-postive metastatic breast cancer.
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PMID:Preclinical and first-in-human phase I studies of KW-2450, an oral tyrosine kinase inhibitor with insulin-like growth factor receptor-1/insulin receptor selectivity. 2685 Jun 78

Studies have suggested that type 2 diabetes (T2D) is associated with a higher incidence of breast cancer and related mortality rates. T2D postmenopausal women have an ~20% increased chance of developing breast cancer, and women with T2D and breast cancer have a 50% increase in mortality compared to breast cancer patients without diabetes. This correlation has been attributed to the general activation of insulin receptor signaling, glucose metabolism, phosphatidylinositol (PI) kinases, and growth pathways. Furthermore, the presence of breast cancer specific PI kinase and/or phosphatase mutations enhance metastatic breast cancer phenotypes. We hypothesized that each of the breast cancer subtypes may have characteristic PI phosphorylation profiles that are changed in T2D conditions. Therefore, we sought to characterize the PI phosphorylation when equilibrated in normal glycemic versus hyperglycemic serum conditions. Our results suggest that hyperglycemia leads to: 1) A reduction in PI3P and PIP3, with increased PI4P that is later converted to PI(3,4)P2 at the cell surface in hormone receptor positive breast cancer; 2) a reduction in PI3P and PI4P with increased PIP3 surface expression in human epidermal growth factor receptor 2-positive (HER2+) breast cancer; and 3) an increase in di- and tri-phosphorylated PIs due to turnover of PI3P in triple negative breast cancer. This study begins to describe some of the crucial changes in PIs that play a role in T2D related breast cancer incidence and metastasis.
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PMID:Using Phosphatidylinositol Phosphorylation as Markers for Hyperglycemic Related Breast Cancer. 3223 Aug 59