Perspectives on the chemical etiology of breast cancer.

Multiple factors, known and unknown, contribute to human breast cancer. Hereditary, hormonal, and reproductive factors are associated with risk of breast cancer. Environmental agents, including chemical carcinogens, are modifiable risk factors to which over 70% of breast cancers have been attributed. Polymorphisms of drug-metabolizing enzymes may influence risk of breast cancer from environmental chemicals, dietary agents, and endogenous steroids. The environmental factors discussed in this review include pollutants, occupational exposures, tobacco smoke, alcohol, and diet. Aromatic amines are discussed as potential mammary carcinogens, with a focus on heterocyclic amine food pyrolysis products. These compounds are excreted into the urine after consumption of meals containing cooked meats and have recently been detected in the breast milk of lactating women

Rac Inhibition Reverses the Phenotype of Fibrotic Fibroblasts

Background: Fibrosis, the excessive deposition of scar tissue by fibroblasts, is one of the largest groups of diseases for which there is no therapy. Fibroblasts from lesional areas of scleroderma patients possess elevated abilities to contract matrix and produce alpha-smooth muscle actin (alpha-SMA), type I collagen and CCN2 (connective tissue growth factor, CTGF). The basis for this phenomenon is poorly understood, and is a necessary prerequisite for developing novel, rational anti-fibrotic strategies.Methods and Findings: Compared to healthy skin fibroblasts, dermal fibroblasts cultured from lesional areas of scleroderma (SSc) patients possess elevated Rac activity. NSC23766, a Rac inhibitor, suppressed the persistent fibrotic phenotype of lesional SSc fibroblasts. NSC23766 caused a decrease in migration on and contraction of matrix, and alpha-SMA, type I collagen and CCN2 mRNA and protein expression. SSc fibroblasts possessed elevated Akt phosphorylation, which was also blocked by NSC23766. Overexpression of rac1 in normal fibroblasts induced matrix contraction and alpha-SMA, type I collagen and CCN2 mRNA and protein expression. Rac1 activity was blocked by PI3kinase/Akt inhibition. Basal fibroblast activity was not affected by NSC23766.Conclusion: Rac inhibition may be considered as a novel treatment for the fibrosis observed in SSc

Cigarette smoking, cytochrome P4501A1 polymorphisms, and breast cancer among African-American and white women

INTRODUCTION: Previous epidemiologic studies suggest that women with variant cytochrome P4501A1 (CYP1A1) genotypes who smoke cigarettes are at increased risk for breast cancer. METHODS: We evaluated the association of breast cancer with CYP1A1 polymorphisms and cigarette smoking in a population-based, case–control study of invasive breast cancer in North Carolina. The study population consisted of 688 cases (271 African Americans and 417 whites) and 702 controls (285 African Americans and 417 whites). Four polymorphisms in CYP1A1 were genotyped using PCR/restriction fragment length polymorphism analysis: M1 (also known as CYP1A1*2A), M2 (CYP1A1*2C), M3 (CYP1A1*3), and M4 (CYP1A1*4) RESULTS: No associations were observed for CYP1A1 variant alleles and breast cancer, ignoring smoking. Among women who smoked for longer than 20 years, a modest positive association was found among women with one or more M1 alleles (odds ratio [OR] = 2.1, 95% confidence interval [CI] = 1.2–3.5) but not among women with non-M1 alleles (OR = 1.2, 95% CI = 0.9–1.6). Odds ratios for smoking longer than 20 years were higher among African-American women with one or more M3 alleles (OR = 2.5, 95% CI = 0.9–7.1) compared with women with non-M3 alleles (OR = 1.3, 95% CI = 0.8–2.2). ORs for smoking in white women did not differ appreciably based upon M2 or M4 genotypes. CONCLUSIONS: Cigarette smoking increases breast cancer risk in women with CYP1A1 M1 variant genotypes and in African-American women with CYP1A1 M3 variant genotypes, but the modifying effects of the CYP1A1 genotype are quite weak

Serine phosphorylation regulates paxillin turnover during cell migration

BACKGROUND: Paxillin acts as an adaptor protein that localizes to focal adhesion. This protein is regulated during cell migration by phosphorylation on tyrosine, serine and threonine residues. Most of these phosphorylations have been implicated in the regulation of different steps of cell migration. The two major phosphorylation sites of paxillin in response to adhesion to an extracellular matrix are serines 188 and 190. However, the function of this phosphorylation event remains unknown. The purpose of this work was to determine the role of paxillin phosphorylation on residues S188 and S190 in the regulation of cell migration. RESULTS: We used NBT-II epithelial cells that can be induced to migrate when plated on collagen. To examine the role of paxillin serines 188/190 in cell migration, we constructed an EGFP-tagged paxillin mutant in which S188/S190 were mutated into unphosphorylatable alanine residues. We provide evidence that paxillin is regulated by proteasomal degradation following polyubiquitylation of the protein. During active cell migration on collagen, paxillin is protected from proteasome-dependent degradation. We demonstrate that phosphorylation of serines 188/190 is necessary for the protective effect of collagen. In an effort to understand the physiological relevance of paxillin protection from degradation, we show that cells expressing the paxillin S188/190A interfering mutant spread less, have reduced protrusive activity but migrate more actively. CONCLUSION: Our data demonstrate for the first time that serine-regulated degradation of paxillin plays a key role in the modulation of membrane dynamics and consequently, in the control of cell motility

Kidney Development in the Absence of Gdnf and Spry1 Requires Fgf10

GDNF signaling through the Ret receptor tyrosine kinase (RTK) is required for ureteric bud (UB) branching morphogenesis during kidney development in mice and humans. Furthermore, many other mutant genes that cause renal agenesis exert their effects via the GDNF/RET pathway. Therefore, RET signaling is believed to play a central role in renal organogenesis. Here, we re-examine the extent to which the functions of Gdnf and Ret are unique, by seeking conditions in which a kidney can develop in their absence. We find that in the absence of the negative regulator Spry1, Gdnf, and Ret are no longer required for extensive kidney development. Gdnf−/−;Spry1−/− or Ret−/−;Spry1−/− double mutants develop large kidneys with normal ureters, highly branched collecting ducts, extensive nephrogenesis, and normal histoarchitecture. However, despite extensive branching, the UB displays alterations in branch spacing, angle, and frequency. UB branching in the absence of Gdnf and Spry1 requires Fgf10 (which normally plays a minor role), as removal of even one copy of Fgf10 in Gdnf−/−;Spry1−/− mutants causes a complete failure of ureter and kidney development. In contrast to Gdnf or Ret mutations, renal agenesis caused by concomitant lack of the transcription factors ETV4 and ETV5 is not rescued by removing Spry1, consistent with their role downstream of both RET and FGFRs. This shows that, for many aspects of renal development, the balance between positive signaling by RTKs and negative regulation of this signaling by SPRY1 is more critical than the specific role of GDNF. Other signals, including FGF10, can perform many of the functions of GDNF, when SPRY1 is absent. But GDNF/RET signaling has an apparently unique function in determining normal branching pattern. In contrast to GDNF or FGF10, Etv4 and Etv5 represent a critical node in the RTK signaling network that cannot by bypassed by reducing the negative regulation of upstream signals