Neonatal Experiences Differentially Influence Mammary Gland Morphology, Estrogen Receptor α Protein Levels, and Carcinogenesis in BALB/c Mice

Abstract

Prevention of breast cancer can be achieved with a better understanding of the factors contributing to normal breast development. Because the breast develops postnatally, alterations in the development and lifetime activity of the neuroendocrine system may set up an environment that increases cancer risk. The present study examined how two neonatal experiences over the first 3 weeks of life influence normal and malignant mammary gland development in female BALB/c mice. Following puberty, both brief (15 minutes) and prolonged (4 hours) daily maternal separations of newborn mice accelerated mammary gland development relative to nonseparated mice. Despite similar mammary gland morphologies between mice exposed to these two neonatal separation experiences, only mice exposed to prolonged maternal separation bouts showed a higher incidence and faster onset of mammary tumorigenesis following adulthood carcinogen [7,12-dimethylbenz(a)anthracene] administration. Molecular analysis of estrogen receptor α (ERα) and p53, two proteins that have been implicated in breast cancer, revealed that for mice exposed to prolonged neonatal maternal separation bouts, mammary gland ERα protein levels were upregulated in a transcription-independent manner. On the other hand, p53 expression in mammary glands of adult mice was not differentially influenced by neonatal experiences. Our findings show that chronic, moderate psychosocial stress during the neonatal period increases the expression of ERα protein and promotes mammary tumorigenesis in adulthood. Cancer Prev Res; 3(11); 1398-408. ©2010 AACR.

CARM1 automethylation is controlled at the level of alternative splicing

“…Although both isoforms are expressed in luminal and stromal compartments, CARM1FL is preferentially expressed in the luminal (epithelial) area of normal mouse mammary glands. The preferential expression of the ERα activity mediating isoform CARM1FL in the epithelial luminal cells may be expected, as we have shown previously that ERα protein levels in normal mouse mammary gland is significantly higher in epithelial (luminal) than in stromal areas (30), and CARM1 levels have been correlated to ERα levels, albeit in ERα-positive tumors (8). Moreover, and in support of our in vitro data, our results show that the automethylated CARM1FL is the predominant isoform in the luminal compartment of normal mouse mammary glands.…”

Persistent upregulation of U6:SNORD44 small RNA ratio in the serum of breast cancer patients

“…In this context, it was recently reported that chronic stress induces epigenetic changes, which impact DNA methylation patterns and consequent effects on gene expression in both germline and somatic tissues [30]. Furthermore, neonatal experiences altering ERα levels in the adult mammary gland and consequent effects on mammary tumor incidence have been reported using animal models [31]. In addition, a recent study showed that individuals with a persistent asymptomatic hepatitis B virus (HBV) infection and patients with active HBV infection share a serum miRNA profile, which is distinct from a healthy individual [32].…”

Psychosocially Influenced Cancer: Diverse Early-Life Stress Experiences and Links to Breast Cancer

“…Two recent such studies, including one from our laboratories, have addressed the interplay between social stress initiated in the peripubertal period (3–6 weeks of age) and mammary tumorigenesis (9, 10). In this issue of the journal, the Kerr laboratory (Boyd et al) reports a related third study, which extends this line of inquiry to early-life stress paradigms induced by neonatal maternal separation (11). Although these studies differ in the stressor and oncogenic stimulus, together they begin to illuminate the complex mechanisms whereby responses to diverse early-life stress experiences can modulate the developmental and oncogenic processes within the mammary gland.…”

“…One consequence of different timing is illustrated by the aforementioned studies in mouse models. The effects of chronic stress initiated in the neonatal period on mammary development are opposite to those of chronic stress initiated during the peripubertal period: neonatal maternal separation increases maturation of the ductal tree (11), whereas post-weaning social isolation reduces it (10). Recent studies have shown that variations during mouse development in the amount of maternal care received program estrogen-receptor (14, 15) and glucocorticoid-receptor (16) expression in brain tissue.…”