One plausible mechanism for the environment to alter cancer susceptibility is through DNA methylation. Alterations in DNA methylation can lead to genomic instability and altered gene transcription. Genomic DNA methylation levels have been inversely associated with age suggesting that factors throughout life may be associated with declines in DNA methylation. Using information from a multi-ethnic New York City birth cohort (born between 1959 and 1963), we examined whether genomic DNA methylation, measured in peripheral blood mononuclear cells, was associated with smoking exposure and other epidemiologic risk factors across the lifecourse. Information on prenatal and childhood exposures was collected prospectively through 1971; and information on adult exposures and blood specimens were collected in adulthood from 2001-2007. Methylation levels of leukocyte DNA were determined using a [3H]-methyl acceptance assay where higher values of DPM/μg DNA indicate less DNA methylation. Genomic methylation of leukocyte DNA differed by ethnicity (66% of blacks, 48% of whites, and 29% of Hispanics were above the median level of DPM/μg DNA) (p = 0.03). In multivariable modeling, DNA methylation was statistically significantly associated with maternal smoking during pregnancy, longer birth length, later age at menarche, nulliparity, and later age at first birth. These data, if replicated in larger samples, suggest that risk factors across the lifecourse may be associated with DNA methylation in adulthood. Larger studies and studies that measure within-individual changes in DNA methylation over time are a necessary next step.

Lesions of ERBB2, PTEN, and PIK3CA activate the phosphatidylinositol 3-kinase (PI3K) pathway during cancer development by increasing levels of phosphatidylinositol-3,4,5-triphosphate (PIP 3 ). 3-Phosphoinositide-dependent kinase 1 (PDK1) is the first node of the PI3K signal output and is required for activation of AKT. PIP 3 recruits PDK1 and AKT to the cell membrane through interactions with their pleckstrin homology domains, allowing PDK1 to activate AKT by phosphorylating it at residue threonine-308. We show that total PDK1 protein and mRNA were overexpressed in a majority of human breast cancers and that 21% of tumors had five or more copies of the gene encoding PDK1, PDPK1. We found that increased PDPK1 copy number was associated with upstream pathway lesions (ERBB2 amplification, PTEN loss, or PIK3CA mutation), as well as patient survival. Examination of an independent set of breast cancers and tumor cell lines derived from multiple forms of human cancers also found increased PDK1 protein levels associated with such upstream pathway lesions. In human mammary cells, PDK1 enhanced the ability of upstream lesions to signal to AKT, stimulate cell growth and migration, and rendered cells more resistant to PDK1 and PI3K inhibition. After orthotopic transplantation, PDK1 overexpression was not oncogenic but dramatically enhanced the ability of ERBB2 to form tumors. Our studies argue that PDK1 overexpression and increased PDPK1 copy number are common occurrences in cancer that potentiate the oncogenic effect of upstream lesions on the PI3K pathway. Therefore, we conclude that alteration of PDK1 is a critical component of oncogenic PI3K signaling in breast cancer. [Cancer Res 2009;69(15):6299-306]

Larger body size in childhood is correlated with earlier age at menarche; whether birth and infant body size changes are also associated with age at menarche is less clear. The authors contacted female participants enrolled in the New York site of the US National Collaborative Perinatal Project born between 1959 and 1963 (n = 262). This racially and ethnically diverse cohort (38% white, 40% African American, and 22% Puerto Rican) was used to investigate whether maternal (body size, pregnancy weight gain, age at menarche, smoking) and birth (birth weight, birth length, placental weight) variables and early infant body size changes were associated with age at menarche even after considering later childhood body size. Higher percentile change in weight from ages 4 months to 1 year was associated with earlier age at menarche even after adjustment for later childhood growth (beta = -0.15, 95% confidence interval: -0.27, -0.02 years per 10-percentile change in weight from ages 4 months to 1 year). The association was in the same direction for all 3 racial/ethnic groups but was largest for the white group. These New York Women's Birth Cohort Adult Follow-up data (2001-2006) suggest that infant weight gain, in addition to childhood weight gain, may be associated with earlier age at menarche.

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