Tumor suppressor p53 is a direct transcriptional activator of the human bax gene

https://www.cell.com/cell/pdf/0092-8674%2893%2990719-7.pdf

p53-dependent apoptosis modulates the cytotoxicity of anticancer agents

During the past decade, possible advancement in timing of puberty has been reported in the United States. In addition, early pubertal development and an increased incidence of sexual precocity have been noticed in children, primarily girls, migrating for foreign adoption in several Western European countries. These observations are raising the issues of current differences and secular trends in timing of puberty in relation to ethnic, geographical, and socioeconomic background. None of these factors provide an unequivocal explanation for the earlier onset of puberty seen in the United States. In the formerly deprived migrating children, refeeding and catch-up growth may prime maturation. However, precocious puberty is seen also in some nondeprived migrating children. Attention has been paid to the changing milieu after migration, and recently, the possible role of endocrine- disrupting chemicals from the environment has been considered. These observations urge further study of the onset of puberty as a possible sensitive and early marker of the interactions between environmental conditions and genetic susceptibility that can influence physiological and pathological processes.

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The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration

Publisher Summary The family of fibroblast growth factors (FGF) is the largest family of growth factors involved in soft–tissue growth and regeneration. The FGF family includes seven members that share a varying degree of homology at the protein level and appear to have a similar broad mitogenic spectrum. They are angiogenic and promote the proliferation of a variety of cells of mesodermal and neuroectodermal origin . Three members of the family–namely, K–FGF/HST, FGF–5, INT–2 are identified originally as oncogenes, while two additions, FGF–6 and keratinocyte growth factor (KGF), are isolated by sequence homology or factor purification and cloning. FGF was identified as an activity in pituitary extracts that stimulated the proliferation of 3T3 cells in mice. The two prototypes of basic and acidic protein structure, the FGF genes, and the expressions of FGF are also discussed. FGF consist of three exons, separated by two introns of variable length and FGF genes map on several chromosomes. The molecular regulation of FGF expression, FGF receptors, and their interaction with extracellular matrix is described. The oncogenic potential of FGF members and their involvement in tumors is also discussed. All possible mechanisms operating on the expression of FGFs and their receptors: transcriptional controls, posttranscriptional regulation involving alternative splicing, alternative translation starts resulting in proteins with different properties, and control affecting the secretion of these proteins are discussed.

The FGF family of growth factors and oncogenes.

PURPOSETo determine the toxicity, pharmacokinetics, response rate, and response duration of intravenous (i.v.) administration of recombinant, humanized anti-p185HER2 monoclonal antibody (rhuMAb HER2) plus cisplatin (CDDP) in a phase II, open-label, multicenter clinical trial for patients with HER2/neu-overexpressing metastatic breast cancer.PATIENTS AND METHODSThe study population consisted of extensively pretreated advanced breast cancer patients with HER2/neu overexpression and disease progression during standard chemotherapy. Patients received a loading dose of rhuMAb HER2 (250 mg i.v.) on day 0, followed by weekly doses of 100 mg i.v. for 9 weeks. Patients received CDDP (75 mg/m2) on days 1, 29, and 57.RESULTSOf 37 patients assessable for response, nine (24.3%) achieved a PR, nine (24.3%) had a minor response or stable disease, and disease progression occurred in 19 (51.3%). The median response duration was 5.3 months (range, 1.6-18). Grade III or IV toxicity was observed in 22 of 39 patients (56%). T...

Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment.

Introduction
Tamoxifen therapy reduces the risk of recurrence and prolongs the survival of oestrogen-receptor-positive patients with breast cancer Even if most patients benefit from tamoxifen, many breast tumours either fail to respond or become resistant Because tamoxifen is extensively metabolised by polymorphic enzymes, one proposed mechanism underlying the resistance is altered metabolism In the present study we investigated the prognostic and/or predictive value of functional polymorphisms in cytochrome P450 3A5 CYP3A5 (*3), CYP2D6 (*4), sulphotransferase 1A1 (SULT1A1; *2) and UDP-glucuronosyltransferase 2B15 (UGT2B15; *2) in tamoxifen-treated patients with breast cancer

/pdf/genetic-variants-of-cyp3a5-cyp2d6-sult1a1-ugt2b15-and-1n00zs25hw.pdf

Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer

Tamoxifen is widely used as endocrine therapy for oestrogen-receptor-positive breast cancer. However, many of these patients experience recurrence despite tamoxifen therapy by incompletely understood mechanisms. In the present report we propose that tamoxifen resistance may be due to differences in activity of metabolic enzymes as a result of genetic polymorphism. Cytochrome P450 2D6 (CYP2D6) and sulfotransferase 1A1 (SULT1A1) are polymorphic and are involved in the metabolism of tamoxifen. The CYP2D6*4 and SULT1A1*2 genotypes result in decreased enzyme activity. We therefore investigated the genotypes of CYP2D6 and SULT1A1 in 226 breast cancer patients participating in a trial of adjuvant tamoxifen treatment in order to validate the benefit from the therapy. The patients were genotyped using PCR followed by cleavage with restriction enzymes. Carriers of the CYP2D6*4 allele demonstrated a decreased risk of recurrence when treated with tamoxifen (relative risk = 0.28, 95% confidence interval = 0.11–0.74, P = 0.0089). A similar pattern was seen among the SULT1A1*1 homozygotes (relative risk = 0.48, 95% confidence interval = 0.21–1.12, P = 0.074). The combination of CYP2D6*4 and/or SULT1A1*1/*1 genotypes comprised 60% of the patients and showed a 62% decreased risk of distant recurrence with tamoxifen (relative risk = 0.38, 95% confidence interval = 0.19–0.74, P = 0.0041). The present study suggests that genotype of metabolic enzymes might be useful as a guide for adjuvant endocrine treatment of postmenopausal breast cancer patients. However, results are in contradiction to prior hypotheses and the present sample size is relatively small. Findings therefore need to be confirmed in a larger cohort.

/pdf/genotype-of-metabolic-enzymes-and-the-benefit-of-tamoxifen-1oa5sxp1vn.pdf

Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients.

Prognostic significance of cytoplasmic p53 oncoprotein in colorectal adenocarcinoma.

The vitamin D3 receptor gene (VDR) contains a TaqI RFLP that is associated with increased VDR mRNA stability, increased serum levels of 1α,25-dihydroxyvitamin D3 (1,25-D3), and decreased risk for p ...

https://cancerres.aacrjournals.org/content/canres/59/10/2332.full.pdf

Sten Wingren

Papers

Genetic variants of CYP3A5, CYP2D6, SULT1A1, UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer

Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients.

Prognostic significance of cytoplasmic p53 oncoprotein in colorectal adenocarcinoma.

Association of Breast Cancer Progression with a Vitamin D Receptor Gene Polymorphism

c-erbB-2 expression and benefit from adjuvant chemotherapy and radiotherapy of breast cancer.