Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to determine the optimal schedule of i.v. granisetron and dexamethosone for control of nausea and emesis in patients receiving high-dose chemotherapy (HDC). Seventy patients with breast cancer received high-dose cyclophosphamide, thiotepa and carboplatin (CTCb) for 3 consecutive days. All 70 received dexamethasone 12 mg i.v. and granisetron 1 mg i.v. prior to infusion of CTCb and were randomized to receive placebo (n = 37) or an additional identical dose of granisetron (n = 33) 12 h later. Beginning on day 2 of chemotherapy administration, 55 patients evaluable later self-administered a cocktail of diphenhydramine (benadryl), lorazepam (ativan) and dexamethasone (BAD). Fourteen of 37 patients (38%) receiving granisetron once a day and 15/33 (44%) receiving it twice a day had a complete response during the first 24 h following the first doses of chemotherapy (P = 0.52). In the 55 evaluable patients receiving BAD, 18 of 29 (62%) in the once daily group and 14/26 (54%) in the twice daily group required additional medications (P = 0.54). The median time to first emetic episode was 20 h (range 6.6-79.5) for patients receiving once a day and 21.4 hours (range 5.8-105.3) for patients receiving twice a day granisetron (P = 0.48). Five patients in the once daily and seven patients in the twice daily group had complete control of nausea and emesis throughout the study period (P = 0.37). It was concluded that there were no statistically significant differences in nausea and emetic control between dexamethasone with once daily or twice daily i.v. granisetron administration in patients receiving high-dose CTCb.
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PMID:A randomized trial of once vs twice daily administration of intravenous granisetron with dexamethosone in patients receiving high-dose cyclophosphamide, thiotepa and carboplatin. 981 97

The PTEN/MMAC1/TEP (PTEN) tumor suppressor gene at 10q23.3 is mutated in multiple types of sporadic tumors including breast cancers and also in the germline of patients with the Cowden's breast cancer predisposition syndrome. The PTEN gene encodes a multifunctional phosphatase capable of dephosphorylating the same sites in membrane phosphatidylinositols phosphorylated by phosphatidylinositol 3'-kinase (PI3K). We demonstrate herein that loss of PTEN function in breast cancer cells results in an increase in basal levels of phosphorylation of multiple components of the P13K signaling cascade as well as an increase in duration of ligand-induced signaling through the P13K cascade. These alterations are reversed by wild-type but not phosphatase inactive PTEN. In the presence of high concentrations of serum, enforced expression of PTEN induces a predominant G1 arrest consistent with the capacity of PTEN to evoke increases in the expression of the p27Kip1 cyclin dependent kinase inhibitor. In the presence of low concentrations of serum, enforced PTEN expression results in a marked increase in cellular apoptosis, a finding which is consistent with the capacity of PTEN to alter the phosphorylation, and presumably function, of the AKT, BAD, p70S6 kinase and GSK3 alpha apoptosis regulators. Under anchorage-independent conditions, PTEN also induces anoikis, a form of apoptosis that occurs when cells are dissociated from the extracellular matrix, which is enhanced in conjunction with low serum culture conditions. Together, these data suggest that PTEN effects on the PI3K signaling cascade are influenced by the cell stimulatory context, and that depending on the exposure to growth factors and other exogenous stimuli such as integrin ligation, PTEN can induce cell cycle arrest, apoptosis or anoikis in breast cancer cells.
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PMID:The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells. 1059 4

AKT1/protein kinase Balpha is a protein-serine/threonine kinase that regulates multiple targets involved in cell survival and cell cycle progression in a variety of cell types including breast cancer cells. To explore the role of Akt1 in mammary gland function and tumorigenesis, transgenic mice were generated that express human AKT1 under the control of the MMTV promoter. Virgin transgenic mice did not exhibit a dominant phenotype, but upon cessation of lactation, a notable delay in involution occurred compared to age-matched non-transgenic mice. The delay in involution coincided with increased hyperplasia as evidenced by an increased number of binucleated epithelial cells and a marked elevation in cyclin D1 expression in mammary epithelium. The delayed involution phenotype corresponded to increased phosphorylation of Thr308 in AKT1 and Ser136 in BAD, but not phosphorylation of Ser21 in GSK-3alpha. There was no evidence of mammary dysplasia or neoplasia during the lifespan of multiparous transgenic mice. These data suggest that AKT1 is involved in cell survival in the lactating and involuting mammary gland, but that overexpression of AKT1 alone is insufficient to induce transformation.
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PMID:Delayed mammary gland involution in MMTV-AKT1 transgenic mice. 1180 63

Novel cancer chemotherapeutics are required to induce apoptosis by activating pro-apoptotic proteins. Both epidermal growth factor (EGF) and insulin-like growth factor (IGF) provide potent survival stimuli in many epithelia, and activation of their receptors is commonly observed in solid human tumors. Here we demonstrate that blockade of the EGF receptor by a new drug in phase III clinical trails for cancer, ZD1839, potently induces apoptosis in mammary epithelial cell lines and primary cultures, as well as in a primary pleural effusion from a breast cancer patient. We identified the mechanism of apoptosis induction by ZD1839. We showed that it prevents cell survival by activating the pro-apoptotic protein BAD. Moreover, we demonstrate that IGF transactivates the EGF receptor and that ZD1839 blocks IGF-mediated phosphorylation of MAPK and BAD. Many cancer therapies kill tumor cells by inducing apoptosis as a consequence of targeting DNA; however, the threshold at which apoptosis can be triggered through DNA damage is often different from that in normal cells. Our results indicate that by targeting a growth factor-mediated survival signaling pathway, BAD phosphorylation can be manipulated therapeutically to induce apoptosis.
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PMID:Activation of BAD by therapeutic inhibition of epidermal growth factor receptor and transactivation by insulin-like growth factor receptor. 1201 Oct 69

Selective estrogen receptor modulator is a proven agent for chemoprevention and chemotherapy of cancer. Raloxifene, a mixed estrogen agonist/antagonist, was developed to prevent osteoporosis and potentially reduce the risk of breast cancer. In this study, we examined the effect of raloxifene on the TSU-PR1 cell line. This cell line was originally reported to be a prostate cancer cell line, but recently it has been shown to be a human bladder transitional cell carcinoma cell line. The TSU-PR1 cell line contains high levels of estrogen receptor beta. Following treatment with raloxifene, evidence of apoptosis, including change in nuclear morphology, DNA fragmentation, and cytochrome c release, was observed in a dose-dependent manner in the TSU-PR1 cells (10(-9) to 10(-6) m range). We observed no detectable change in the steady-state levels of Bax, Bcl-2, and Bcl-X(L) following raloxifene treatment. However, raloxifene induced caspase-dependent cleavage of BAD to generate a 15-kDa truncated protein. Overexpression of a double mutant BAD resistant to caspase 3 cleavage blocked raloxifene-induced apoptosis. These results demonstrate that raloxifene induces apoptosis through the cleavage of BAD in TSU-PR1 cells. This molecular mechanism of apoptosis suggests that raloxifene may be a therapeutic agent for human bladder cancer.
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PMID:Raloxifene, a mixed estrogen agonist/antagonist, induces apoptosis through cleavage of BAD in TSU-PR1 human cancer cells. 1208 14

The major goal in cancer treatment is the eradication of tumor cells. Under stress conditions, normal cells undergo apoptosis; this property is fortunately conserved in some tumor cells, leading to their death as a result of chemotherapeutic and/or radiation-induced stress. Many malignant cells, however, have developed ways to subvert apoptosis, a characteristic that constitutes a major clinical problem. Gilmore et al. recently described the ability of ZD1839, a small-molecule inhibitor of the epidermal growth factor receptor (EGFR), to induce apoptosis of mammary cells that are dependent upon growth factors for survival. Furthermore, they showed that the major effector of the EGFR-targeted therapy is BAD, a widely expressed BCL-2 family member. These results are promising in light of the role of the EGFR in breast cancer development.
Breast Cancer Res 2003
PMID:BAD: a good therapeutic target? 1255 42

Soy isoflavone, genistein has been shown to induce growth inhibition, cell cycle arrest and apoptosis in cultured cancer cell lines derived from head and neck, breast, lung, and prostate cancers and showed antitumor activity against tumors in multiple animal models. In the present study we show that genistein inhibits the growth of MCF-7 breast cancer cell line in a dose dependent manner. The genistein induced growth inhibition is accompanied by the reduction in the number of mitotic cells and overexpression of cyclin dependent kinase inhibitor p21WAF1 leading to cell cycle arrest. In addition, the telomeric area was significantly reduced in genistein treated MCF-7 cells. Analysis of multiple genes involving the apoptotic pathway reveals inhibition of Akt activity without affecting the steady state levels of Akt protein expression and the down regulation of proapoptotic gene BAD expression. From these results, we conclude that genistein-induced inhibition of cell division is partly mediated by decreased telomere length, reduced mitosis and inhibition of Akt activation, leading to induction of apoptosis.
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PMID:Pleotropic effects of genistein on MCF-7 breast cancer cells. 1279 5

Estrogens such as 17-beta estradiol (E(2)) play a critical role in sporadic breast cancer progression and decrease apoptosis in breast cancer cells. Our studies using estrogen receptor-positive MCF7 cells show that E(2) abrogates apoptosis possibly through phosphorylation/inactivation of the proapoptotic protein BAD, which was rapidly phosphorylated at S112 and S136. Inhibition of BAD protein expression with specific antisense oligonucleotides reduced the effectiveness of tumor necrosis factor-alpha, H(2)O(2), and serum starvation in causing apoptosis. Furthermore, the ability of E(2) to prevent tumor necrosis factor-alpha-induced apoptosis was blocked by overexpression of the BAD S112A/S136A mutant but not the wild-type BAD. BAD S112A/S136A, which lacks phosphorylation sites for p90(RSK1) and Akt, was not phosphorylated in response to E(2) in vitro(.) E(2) treatment rapidly activated phosphatidylinositol 3-kinase (PI-3K)/Akt and p90(RSK1) to an extent similar to insulin-like growth factor-1 treatment. In agreement with p90(RSK1) activation, E(2) also rapidly activated extracellular signal-regulated kinase, and this activity was down-regulated by chemical and biological inhibition of PI-3K suggestive of cross talk between signaling pathways responding to E(2). Dominant negative Ras blocked E(2)-induced BAD phosphorylation and the Raf-activator RasV12T35S induced BAD phosphorylation as well as enhanced E(2)-induced phosphorylation at S112. Chemical inhibition of PI-3K and mitogen-activated protein kinase kinase 1 inhibited E(2)-induced BAD phosphorylation at S112 and S136 and expression of dominant negative Ras-induced apoptosis in proliferating cells. Together, these data demonstrate a new nongenomic mechanism by which E(2) prevents apoptosis.
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PMID:Estradiol abrogates apoptosis in breast cancer cells through inactivation of BAD: Ras-dependent nongenomic pathways requiring signaling through ERK and Akt. 1512 78

Phosphorylation of BCL-2 family member BAD at different residues triggers different physiological effects, either inhibiting or promoting apoptosis. The recently identified phosphorylation site at Ser-128 enhances the apoptotic activity of BAD. We here show that BAD becomes phosphorylated at Ser-128 in the mitotic phase of the cell cycle in NIH3T3 cells. We also show that BAD-S128 is phosphorylated in taxol-treated mouse fibroblasts and MDA-MB-231 human breast cancer cells. However, expression of a phosphorylation-defective dominant negative BAD mutant did not block taxol-induced apoptosis. These data support the view that the phosphorylation of BAD Serine 128 exerts cell-specific effects on apoptosis. Whereas the BAD Serine 128 phosphorylation induces apoptosis in neuronal cells, it does not appear to promote apoptosis in proliferating non-neural cells during mitosis or upon exposure to the antineoplastic agent taxol.
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PMID:Phosphorylation of BAD at Ser-128 during mitosis and paclitaxel-induced apoptosis. 1590 27

The protein kinase, PAK1, is overexpressed in human breast cancer and may contribute to malignancy through induction of proliferation and invasiveness. In this study, we examined the role of PAK1 in the survival of detached MCF10A breast epithelial cells to test whether it may also regulate the early stages of neoplasia. MCF10A cells undergo anoikis, as measured by the cleavage of caspase 3 and poly(ADP-ribose) polymerase (PARP), after more than 8 hours of detachment. Endogenous Akt, PAK1, and BAD are phosphorylated in attached MCF10A cells, but these phosphorylation events are all lost during the first 8 hours of detachment. Expression of constitutively active PAK1 or Akt suppresses the cleavage of caspase 3 and PARP in detached MCF10A cells. Co-overexpression of active PAK1 with dominant-negative Akt, or of active Akt with dominant-negative PAK1, still suppresses anoikis. Thus, Akt and PAK1 enhance survival through pathways that are at least partially independent. PAK1-dependent regulation of anoikis is likely to occur early in the apoptotic cascade as expression of dominant-negative PAK1 increased the cleavage of the upstream caspase 9, while constitutively active PAK1 inhibited caspase 9 activation. These results support a role for activated PAK1 in the suppression of anoikis in MCF10A epithelial cells.
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PMID:Active p21-activated kinase 1 rescues MCF10A breast epithelial cells from undergoing anoikis. 1602 43


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