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Adult physical activity is associated with reduced breast cancer risk, but few studies have evaluated activity before adulthood. Early life may be an important period because of rapid breast development and hormonal changes. This study contributes new information by examining childhood (ages 5–12) and teenage (ages 13–19) activity separately and overall. The Sister Study is a cohort of 50,884 women aged 35–74. Women reported age 5–19 sports/exercise activities and age 10 and 16 unstructured activities. Both hours and MET-hours of activity were considered in association with breast cancer overall, by ER status, and by menopausal status. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with Cox proportional hazards models. 2416 cases were diagnosed during follow-up (mean = 6.4 years). Participation in 7+ hours (vs

IGF1 and IGF2 are circulating peptide hormones and locally-acting growth factors with both paracrine and autocrine functions. IGF1 and IGF2 signal through a common tyrosine kinase receptor, the insulin-like growth factor 1 receptor (IGF1R), and have mitogenic, cell survival, and insulin-like actions that are essential for embryogenesis, post-natal growth physiology, and breast development. The activities of IGF1 and 2 are tightly-regulated by a network of binding proteins and targeted degradation mechanisms. This complex regulatory system is disrupted in breast cancer, leading to excess IGF1R signaling. Evidence for this statement includes: a) breast cancers are infiltrated with IGF2 expressing stromal cells; b) mannose 6-phosphate/IGF2 receptor (M6P/IGF2R) is mutated in breast cancer, leading to loss of IGF2 degradation; c) IGF1R is overexpressed by malignant breast epithelial cells, and in some cases IGF1R is amplified; and d) complex changes in IGF binding protein expression occur during breast cancer progression which most likely also affect IGF1 and 2 signaling. The clinical importance of these epigenetic and genetic changes has recently been stressed by the finding that IGF1R signaling alters the apoptotic response of breast cancer cells to genotoxic stress and, in addition, IGF1R activation sensitizes cells to estrogen by inducing phosphorylation of the estrogen receptor. As a consequence of these findings, we propose that IGF analysis of breast cancer samples should shift from prognostic studies to an evaluation of IGF ligands, receptors, and binding proteins as resistance/sensitivity markers for radiation, chemotherapy, and endocrine therapy.

The typical high fat, low fibre diet of the industrialised West, particularly when associated with inadequate exercise, is likely to advance the onset of puberty. This will manifest in girls as an earlier menarche, earlier onset of breast development, and an earlier growth spurt. Both earlier menarche and adult tallness are markers of increased risk to breast cancer. Earlier menarche in the West is usually associated with earlier onset of hyperinsulinaemia, and multiple case-control studies report that hyperinsulinaemia too is a marker of increased breast cancer risk. Although the Western diet is linked both to earlier menarche and also to earlier hyperinsulinaemia, the mechanism involved is not necessarily the same. While menarche is likely to be triggered by a threshold level of fatness, manifestation of insulin resistance is genetically-determined and strongly influenced by the fatty acid profile of the diet. The putative mechanisms by which they influence mammary carcinogenesis also differ. Early menarche is reported to be associated with a raised oestradiol level persisting into early adult life. On the other hand, hyperinsulinaemia is commonly associated with abnormal aromatase activity in the ovaries. In addition, the concomitant increase in bioactive levels of insulin-like growth factor-I may synergise with oestrogen in stimulating proliferative activity in mammary epithelium. Dietary modification and exercise regimens are proposed in families at high risk to breast cancer. The measures have been shown to reduce insulin levels in both children and adults, and serial monitoring of insulin and sex steroid levels could be used to detect a metabolic-endocrine effect.

Although studies of the estrogen receptor gene abound in rodent models and breast cancer cell lines, little is known about expression of this gene in normal human breast. Information regarding the physiology of this gene's expression is important if we are to elucidate abnormalities of the gene that may be involved in breast carcinogenesis. We evaluated levels of mRNA expression of the estrogen receptor (ER) gene and its protein product in a set of 89 breasts from clinically normal female infants, children, adolescents, and adult premenopausal and post-menopausal women. mRNA expression of the gene varied with the hormonal status. Relatively higher levels of gene transcripts were found in breasts of peri-menarchal girls, women in the luteal phase of the menstrual cycle, and in those with fibrocystic change. Higher levels were also occasionally found in breasts of infants and in most pre-adolescent children. Lower levels were seen in breasts of women in the follicular phase of the menstrual cycle, during pregnancy, and after menopause. Nuclear protein staining was common in breasts of normal children and peri-menarchal adolescents, and in post-menopausal atrophic breasts. Nuclear ER protein was infrequently detected in reproductive aged women's breasts, but was more often seen in follicular than in luteal menstrual phase or pregnant breast. ER protein was more frequently seen in post-menopausal than in pre-menopausal breasts with fibrocystic change. The results fit a model in which circulating levels of estrogen are inversely related to levels of mRNA transcribed from the estrogen receptor gene in normal physiologic states. Abnormally high levels of gene transcription may occur in some cases of fibrocystic change.

Measurement of breast tissue estradiol levels could provide a powerful method to predict the risk of developing breast cancer but obtaining sufficient amounts of tissue from women is difficult from a practical standpoint. Assessment of aromatase in ductal lavage fluid or fine needle aspirates from breast might provide a surrogate marker for tissue estrogen levels but highly sensitive methods would be required. These considerations prompted us to develop an ultra-sensitive, “nested” PCR assay for aromatase which is up to one million fold more sensitive than standard PCR methods. We initially validated this assay using multiple tissues from the aromatase transgenic mouse and found that coefficients of variation for measurement of replicate samples averaged less than 5%. We demonstrated a 60-fold enhancement in aromatase message in the transgenic versus the wild type mouse breast but surprisingly, levels in the transgenic animals were highly variable, ranging from 0.4 to 27 relative units. The variability of aromatase expression in the transgenic breast did not correlate with the degree of breast development and did not appear to relate to hormonal manipulation of the MMTV promoter but probably related to lack of exhaustive inbreeding and mixed zygocity of transgenic animals. Extensive validation in mouse tissues provided confidence regarding the assay in human tissues, since nearly identical methods were used. The human assay was sufficiently sensitive to detect aromatase in a single human JAR (choriocarcinoma) cell, in all breast biopsies measured, and in 7/23 ductal lavage fluids.