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The insulin-like growth factor-1 (IGF-1) signaling pathway has been implicated in non-small cell lung cancer (NSCLC) outcomes and resistance to targeted therapies. However, little is known regarding the molecular mechanisms by which this pathway contributes to the biology of NSCLC. The insulin receptor substrate (IRS) proteins are cytoplasmic adaptor proteins that signal downstream of the IGF-1R and determine the functional outcomes of this signaling pathway. In this study, we assessed the expression patterns of IRS-1 and IRS-2 in NSCLC to identify associations between IRS-1 and IRS-2 expression levels and survival outcomes in the two major histological subtypes of NSCLC, adenocarcinoma (ADC) and squamous cell carcinoma (SCC). High IRS-2 expression was significantly associated with decreased overall survival in adenocarcinoma (ADC) patients, whereas low IRS-1 cytoplasmic expression showed a trend toward association with decreased overall survival in squamous cell carcinoma (SCC) patients. Tumors with low IRS-1 and high IRS-2 expression were found to be associated with poor outcomes in ADC and SCC, indicating a potential role for IRS-2 in the aggressive behavior of NSCLC. Our results suggest distinct contributions of IRS-1 and IRS-2 to the biology of ADC and SCC that impact disease progression. [ABSTRACT FROM AUTHOR]

There is evidence of poor prognosis in women with pregnancy‐associated breast cancer (PABC) diagnosed during pregnancy or within 2 years of delivery. Using a large, population‐based cohort, we examined clinicopathologic features and survival in women with PABC. A cohort of women diagnosed with invasive breast cancer between 1992 and 2009 at ages 15–44 years was identified in the Swedish Cancer Register and the Breast Cancer Quality Registers. Dates of childbirths for each woman were retrieved from the Swedish Multi‐Generation Register. Age‐standardized distributions of tumor stage (tumor size, nodal status, metastasis), Elston grade and ER/PR/HER2 status were compared between nulliparous women and women with breast cancer during pregnancy and up to 10 years postdelivery. Adjusted hazard ratios for all‐cause mortality rates among patients were estimated using Cox regression. We identified 1,661 nulliparous women with breast cancer, 778 women with PABC (97 during pregnancy, 270 within first and 411 within second year postdelivery) and 3,598 during 2–10 years postdelivery. Compared to nulliparous women, women with PABC, and especially women diagnosed 0–12 months after delivery, had more advanced T and N stage, and higher proportions of ER/PR negative, HER2 positive and triple‐negative tumors. Increased hazard ratios were observed in women diagnosed within 5 years of delivery after adjustment for age, year, education and region. Following additional adjustment for tumor characteristics, the hazard ratios were attenuated and nonsignificant. The poorer prognosis observed in women with PABC appears to be largely explained by more adverse tumor characteristics at diagnosis. [ABSTRACT FROM AUTHOR]

Literature about the risk of secondary cancer after radiation therapy (RT) of prostate and rectal cancer reveals contradictory results. We conducted a meta-analysis to examine whether the RT induces secondary rectal or prostate cancer in patients, respectively, with prostate or rectal cancer. All studies published in Medline or Pubmed up to March 3, 2015, containing RT of primary rectal or prostate cancer, and providing risk estimates of secondary prostate or rectal cancer were considered as eligible. Relative risk (RR) and standardized incidence ratios (SIR) were calculated using the random-effects model. Twenty studies met the inclusion criteria. 12 of them were from the Surveillance, Epidemiology, and End Results (SEER) database. For prostate cancer patients, pooled adjusted RRs or SIRs did not show an effect on the risk of secondary rectal cancer. However, notwithstanding the limitations of SEER-based studies, the subgroup of prostate cancer patients receiving external beam radiation therapy (EBRT) showed an increased risk of rectal cancer. For rectal cancer patients, pooled adjusted RR of prostate cancer was 1.12 (95 % CI, 0.44-2.8) and SIR was 0.40 (95 % CI, 0.29-0.55). All studies included in the SIR analysis of rectal cancer were derived from the SEER data source. Based on current evidence, RT for prostate cancer patients had no effect on rectal cancer incidence, except for patients who received EBRT therapy. However, compared with the general population, RT for rectal cancer is associated with a decreased prostate cancer risk as found in SEER-based studies. [ABSTRACT FROM AUTHOR]

The risk of breast cancer is at least two-fold increased in young women with a family history of breast cancer. Pregnancy has a dual effect on breast cancer risk; a short-term increase followed by a long-term protection. We investigated if the risk of breast cancer during and within 10 years following pregnancy is affected by a family history of breast cancer. We followed a cohort of women aged 15-44 years between 1963 and 2009 identified in Swedish population-based registers. Family history was defined as having a mother or sister with breast cancer. We estimated incidence rate ratios of breast cancer during pregnancy and time intervals up to 10 years post-delivery, with a focus on pregnancy-associated breast cancer (PABC), defined as breast cancer during pregnancy or within 2 years post-delivery. In 3,452,506 women, there were 15,548 cases of breast cancer (1208 were PABC). Compared to nulliparous women, the risk of breast cancer was decreased during pregnancy, similar during first year and increased during second year post-delivery. The pattern was similar in women with or without family history of breast cancer. A peak in risk was observed 5-6 years following the first birth regardless of family history. After a second birth, this peak was only present in women with a family history. Our results indicate that women with a family history of breast cancer do not have a different breast cancer risk during and within 10 years following pregnancy compared to women without a family history. [ABSTRACT FROM AUTHOR]

Women born from a preeclamptic pregnancy are associated with a lower risk of breast cancer. Umbilical cord blood samples from pregnancies complicated by preeclampsia had significantly lower levels of hematopoietic, endothelial and putative breast stem cells than normotensive controls.Women born from a preeclamptic (PE) pregnancy are associated with a lower risk of breast cancer. Prenatal and early-life exposures are hypothesized to influence breast cancer susceptibility through their effect on stem cells. We examined stem cell populations in umbilical cord blood from PE pregnancies and compared with those from pregnancies without this condition. We isolated mononuclear cells from 58 PE and 197 normotensive (non-PE) umbilical cord blood samples and examined the different stem cell populations. Hematopoietic (CD34+ and CD34+CD38−), endothelial (CD34+CD133+, CD34+VEGFR2+, CD133+VEGFR2+ and CD34+CD133+VEGFR2+), and putative breast (EpCAM+, EpCAM+CD49f+, EpCAM+CD49f+CD117+, CD49f+CD24+, CD24+CD29+ and CD24+CD29+CD49f+) stem/progenitor cell subpopulations were quantified by flow cytometry and compared between PE and non-PE samples. Hematopoietic CD34+ cell counts were significantly lowered in PE compared with non-PE samples (P = 0.039, Kruskal–Wallis test). Levels of CD34+CD133+ endothelial progenitor cells were also lower in PE samples (P = 0.032, multiple regression analysis). EpCAM+ and EpCAM+CD49f+ putative breast stem cell levels were significantly lowered in PE subjects (multiple regression analysis: P = 0.038 and 0.007, respectively). Stratifying by newborn gender, EpCAM+ and EpCAM+CD49f+ stem cells were significantly lowered in PE samples of female, but not male, newborns. Umbilical cord blood samples from pregnancies complicated by preeclampsia thus had significantly lower levels of hematopoietic, endothelial, and putative breast stem cells than non-PE controls. With a lowered breast cancer risk for offspring of a PE pregnancy, our findings provide support to the hypothesis that susceptibility to breast oncogenesis may be affected by conditions and processes during the prenatal period. [ABSTRACT FROM AUTHOR]

The main aim of this study was to investigate possible associations between measures of offspring size at birth in the most recent pregnancy before premenopausal breast cancer diagnosis and the risks of maternal breast cancer mortality, taking tumor characteristics into account. We also aimed to investigate if these associations are modified by age at childbirth, time since childbirth, parity, and age at diagnosis. We followed 6,019 women from their date of premenopausal breast cancer (diagnosed from 1992 to 2008) until emigration, death or December 31st, 2009, whichever occurred first. We used Cox proportional hazard regression models, adjusted for parity, age at diagnosis, and education level, to estimate associations between women pregnancy, cancer characteristics and offspring birth characteristics, and mothers' mortality risk. In stratified analyses, mortality risks were estimated by tumor stage, ER or PR status. There was no association between offspring birth weight (HR = 1.00, 95 % CI 0.99-1.01, when used as a continuous variable), birth weight for gestational age or ponderal index, and premenopausal breast cancer mortality. Similarly, in analyses stratified by tumor stage, receptor status, and time difference between last pregnancy and date of diagnosis, we found no associations between birth size and breast cancer mortality. Our findings suggest that the hypothesis that 'premenopausal breast cancer mortality is associated with offspring birth characteristics in the most recent pregnancy before the diagnosis' may not be valid. In addition, these associations are not modified by tumor characteristics. [ABSTRACT FROM AUTHOR]

Birth size has been associated with adult life diseases, but the endocrine factors that are likely involved are not established. We evaluated the associations of maternal and cord blood hormones with birth size in normal pregnancies, and examined possible effect modification by maternal height, on the basis of prior suggestive evidence. In a prospective study of normal singleton pregnancies in Boston, USA and Shanghai, China, maternal hormone levels at the 27th gestational week were available for 225 pregnancies in Boston and 281 in Shanghai and cord blood measurements for 92 pregnancies in Boston and 110 in Shanghai. Pearson partial correlation coefficients of log-transformed hormone levels with birth weight and length were calculated. Overall, positive correlations with birth weight were found for maternal estriol (r = 0.19; p < 0.001) and progesterone (r = 0.15; p < 0.001) and these associations were more evident among taller mothers. There was an inverse association of cord blood progesterone (r = −0.16; p < 0.03) with birth weight. In Boston, cord blood IGF-1 was positively associated with birth weight (r = 0.22; p < 0.04) and length (r = 0.25; p < 0.02), particularly among taller mothers (r = 0.43 and 0.38, respectively; p < 0.02), whereas among taller mothers in Shanghai the associations of IGF-2 with birth size appeared to be at least as strong as those of IGF-1. In conclusion, maternal estriol and progesterone, and cord blood IGF-1 were positively correlated with birth size. All correlations tended to be more pronounced among offspring of taller mothers. Among taller mothers in Shanghai, IGF-2 appeared to be at least as strongly associated with birth size as IGF-1. [ABSTRACT FROM AUTHOR]

This study was carried out to dissect the mechanism by which β1 integrins promote resistance to radiation. For this purpose, we conditionally ablated β1 integrins in the prostatic epithelium of transgenic adenocarcinoma of mouse prostate (TRAMP) mice. The ability of β1 to promote resistance to radiation was also analyzed by using an inhibitory antibody to β1, AIIB2, in a xenograft model. The role of β1 integrins and of a β1 downstream target, c-Jun amino-terminal kinase 1 (JNK1), in regulating radiation-induced apoptosis in vivo and in vitro was studied. We show that β1 integrins promote prostate cancer (PrCa) progression and resistance to radiation in vivo. Mechanistically, β1 integrins are shown here to suppress activation of JNK1 and, consequently apoptosis, in response to irradiation. Downregulation of JNK1 is necessary to preserve the effect of β1 on resistance to radiation in vitro and in vivo. Finally, given the established crosstalk between β1 integrins and type1 insulin-like growth factor receptor (IGF-IR), we analyzed the ability of IGF-IR to modulate β1 integrin levels. We report that IGF-IR regulates the expression of β1 integrins, which in turn confer resistance to radiation in PrCa cells. In conclusion, this study demonstrates that β1 integrins mediate resistance to ionizing radiation through inhibition of JNK1 activation. J. Cell. Physiol. 228: 1601-1609, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Converging evidence indicates that women with pregnancy-associated breast cancer (PABC) have increased mortality compared to women with breast cancer not diagnosed near pregnancy (non-PABC). Our aim was to investigate if the stage distribution differs between PABC and non-PABC and if stage at diagnosis can explain the poorer prognosis observed among women with PABC. We identified 3,282 breast cancers in women aged 15-44 years at diagnosis for whom staging data (tumor size, nodal involvement, metastasis) were available in the Swedish Cancer Register between 2002 and 2009. Information on reproductive history and vital status was obtained from the Multi-Generation Register and the Cause of Death Register. PABC was defined as breast cancers diagnosed during pregnancy and up to 2 years after delivery ( n = 317). Non-PABC was defined as cases diagnosed before pregnancy or more than 2 years postpartum. Stage distributions were compared between PABC and non-PABC, and mortality rates were modeled using Cox regression. Compared to women with non-PABC, the mortality was almost 50 % higher in women with PABC [unadjusted hazard ratio (HR) 1.47 (95 % CI 1.04-2.08)], a difference which was reduced after adjustment for age and calendar year of diagnosis [HR 1.27 (95 % CI 0.88-1.83)]. Although advanced stage of breast cancer at diagnosis was more common among PABC than among non-PABC, further adjustment for stage only slightly reduced the HR [1.22 (95 % CI 0.84-1.78)]. The difference in mortality between PABC and non-PABC was more pronounced among women above 35 years and among women with PABC diagnosed within 1 year postpartum. Age, rather than stage at diagnosis, appears to act as the principal driver of the increased mortality observed in women with PABC. However, these findings do not preclude an untoward influence on mortality by pregnancy-associated factors affecting tumor aggressiveness and progression. [ABSTRACT FROM AUTHOR]

Background: Mutations in FGFR3 have been shown to occur in tumors of the upper urothelial tract and may be indicative of a good prognosis. In bladder tumors, the combination of FGFR3 mutation status and Ki-67 level has been used to define a tumor's molecular grade and predict survival. Pathological evaluation of upper urothelial tumors is currently the best predictor of prognosis, but suffers from variability in pathological assessments. This study investigated the association with prognosis of FGFR3 mutations alone and in combination with Ki-67 in this patient population. Methods: Genomic DNA was isolated from tumor samples of 80 patients with upper urothelial cancer. The presence of mutation in FGFR3 was evaluated using real-time polymerase chain reaction. Ki-67 protein expression was determined by immunohistochemistry. Kaplan-Meier survival analysis evaluated the relationship of FGFR3 mutations and Ki-67 levels with survival. Results: FGFR3 mutations were identified in 40% of tumors and were predominantly associated with noninvasive tumors. Overall survival was higher in patients with FGFR3 mutant tumors (P = 0.02) and in molecular grade 1 tumors as determined by FGFR3 and Ki-67 (P = 0.02). Conclusion: In this study, we confirm the occurrence of FGFR3 mutations in tumors of the upper urothelial tract and its association with a good prognosis. Both FGFR3 and molecular grading are predictors of overall survival. Molecular grading can help to assess the prognosis of patients with upper urinary tract cancer and may represent a new tool for managing this population of patients. [ABSTRACT FROM AUTHOR]

Recent studies have identified a role for insulin receptor substrate-2 (IRS-2) in promoting motility and metastasis in breast cancer. However, no published studies to date have examined IRS-2 expression in human breast tumors. We examined IRS-2 expression by immunohistochemistry (IHC) in normal breast tissue, benign breast lesions, and malignant breast tumors from the institutional pathology archives and a tumor microarray from a separate institution. Three distinct IRS-2 staining patterns were noted: diffusely cytoplasmic, punctate cytoplasmic, and localized to the cell membrane. The individual and pooled datasets were analyzed for associations of IRS-2 staining pattern with core clinical parameters and clinical outcomes. Univariate analysis revealed a trend toward decreased overall survival (OS) with IRS-2 membrane staining, and this association became significant upon multivariate analysis ( P = 0.01). In progesterone receptor negative (PR−) tumors, in particular, IRS-2 staining at the membrane correlated with significantly worse OS than other IRS-2 staining patterns ( P < 0.001). When PR status and IRS-2 staining pattern were evaluated in combination, PR− tumors with IRS-2 at the membrane were associated with a significantly decreased OS when compared with all other combinations ( P = 0.002). Evaluation of IRS-2 staining patterns could potentially be used to identify patients with PR− tumors who would most benefit from aggressive treatment. [ABSTRACT FROM AUTHOR]

Male newborns are somewhat heavier than female ones and it has been reported, in a Caucasian population, that mothers carrying boys have higher energy intake during pregnancy compared to those carrying girls. In the context of a prospective study comprising 150 Caucasian women in Boston, USA and 243 Asian women in Shanghai China, energy intake at the second trimester of pregnancy was estimated based on center-specific food frequency questionnaires. There was a significant interaction ( P = 0.01) of maternal height with offspring gender with respect to maternal daily energy intake. Among taller women, male gender of the offspring was associated with higher maternal energy intake (difference 341 kcal/day, 95% Confidence Interval 77-604; P = 0.01), whereas among shorter women, no significant association existed between offspring gender and maternal daily energy intake (difference −213 kcal/day, 95% Confidence Interval −479 to 54; P = 0.12). Our findings indicate that the higher somatic growth potential of boys in intrauterine life is realized only when there are no constrains imposed by maternal anthropometry and it is, then, associated with higher maternal energy intake during pregnancy. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to examine factors influencing a woman's decision to participate in a breast cancer prevention clinical trial. Nine healthcare organizations in Massachusetts cooperated in the present project.Methods: The authors performed a case-control study to compare responses between the study group (Study of Tamoxifen and Raloxifene [STAR] trial eligible, but not enrolled) and the control group (STAR trial participants) on 12 factors previously identified as barriers to accrual for clinical trials. Eight hypotheses were tested using multiple logistic regression to estimate the strength of the association for each factor on the dependent variable (study participation).Results: The study samples were similar to the general population of eligible breast cancer prevention clinical trial subjects in the counties where the participating organizations were located, the state of Massachusetts, and nationally published STAR trial data. Results of a mailed questionnaire showed that when adjusting for subject demographics, and in the presence of other questions, 4 factors significantly influenced a woman's decision to enroll onto a breast cancer prevention clinical trial more than other eligible subjects: 1) clinician expertise and qualifications (P=.012; odds ratio [OR], 4.903; 95% confidence interval [CI], 1.41-17.04); 2) personal desire to participate (P=.033; OR, 3.16; 95% CI, 1.10-9.06); 3) perceived value of the trial (P=.020; OR, 2.92; 95% CI, 1.18-7.21); and 4) level of trial inconvenience (P=.002; OR, 0.10; 95% CI, 0.02-0.44).Conclusions: Addressing these issues in the relationship between patients and clinicians should improve accrual to breast cancer prevention clinical trials. [ABSTRACT FROM AUTHOR]

The article discusses a study on the factors that influence a woman to participate or not in a breast cancer prevention clinical trial. Healthcare organizations in five counties of Massachusetts participated in the project with 242 women found to be eligible for the study. A 29-question mailed survey instruments was done and responses were compared. It is concluded that a patient-clinician relationship is important in accrual into breast cancer prevention clinical trials and that a positive relationship helps reduce the barrier of trial inconvenience.

There is considerable evidence that birth weight is positively associated with breast cancer risk, and seven single-nucleotide polymorphisms (SNPs) have been conclusively associated with this risk. We have hypothesized that breast cancer susceptibility loci may have a greater influence on breast cancer risk among women with higher birth weight, who are expected to have a larger pool of mammary stem cells that are susceptible to malignant transformation. In the context of a nationwide, population-based case–control study in Sweden, we retrieved recorded birth weight for 693 breast cancer cases and 747 control women who were also genotyped for most or all of the seven recently documented breast cancer susceptibility SNPs: rs2981582, rs12443621, rs8051542, rs3803662, rs889312, rs13281615, and rs3817198. We grouped heterozygotes with homozygotes for the wild-type allele, and we found a marginally significant interaction ( p~0.07) between birth weight and rs2981582 (FGFR2), the genotype repeatedly identified as the top hit in genome-wide association studies. There were similar, though not significant, patterns for the other six SNPs. Although our findings require confirmation, we found suggestive evidence that genetic susceptibility modifies the positive association of birth weight with breast cancer. [ABSTRACT FROM AUTHOR]

Epidemiologic studies suggest positive associations between poor oral health and cardiovascular disease. The authors undertook a prospective study among 15,273 Swedish twins (1963–2000) to examine whether genetic factors underlying the 2 diseases could explain previous associations. They estimated hazard ratios and 95% confidence intervals controlling for individual factors and stratifying on twin pairs to control for familial effects. Quantitative genetic analyses estimated genetic correlations between oral diseases and cardiovascular disease outcomes. Tooth loss (hazard ratio (HR) = 1.2, 95% confidence interval (CI): 1.1, 1.4) and periodontal disease (HR = 1.3, 95% CI: 1.0, 1.4) were associated with small excess risks of cardiovascular disease; periodontal disease was also associated with coronary heart disease (HR = 1.4, 95% CI: 1.1, 1.6). Adjustment for genetic factors in co-twin analyses did not appreciably change estimates. In contrast, tooth loss was more strongly associated with coronary heart disease in twin models (HR = 2.1, 95% CI: 1.2, 3.8) compared with adjusting for individual factors alone (HR = 1.3, 95% CI: 1.1, 1.4). There was evidence of shared genetic factors between cardiovascular disease and tooth loss (rG = 0.18) and periodontal disease (rG = 0.29). Oral disease was associated with excess cardiovascular disease risk, independent of genetic factors. There appear to be common pathogenetic mechanisms between poor oral health and cardiovascular disease. [ABSTRACT FROM PUBLISHER]

Objective: It has been recently reported that expression of estrogen alpha (ER-alpha) and progesterone (PR) receptors in the normal mammary gland is inversely associated with breast cancer risk among postmenopausal women. We investigated whether dietary intakes are associated with the expression of ER-alpha and PR receptors in the apparently normal, as opposed to pathological, mammary tissue.Methods: In a study in Greece, we examined associations of dietary intakes with ER-alpha and PR expression in the adjacent-to-pathological apparently normal mammary tissue of 562 women with either breast cancer (267 women) or BBD (299 women). Diet was assessed through an extensive food frequency questionnaire and results were analyzed using multiple logistic regression.Results: Monounsaturated (p = 0.03) and, to a lesser extent, polyunsaturated lipids (p = 0.08) were positively associated with ER-alpha expression. Cereals and starchy roots were inversely associated with ER-alpha (p = 0.01), whereas milk and dairy products were inversely associated with PR expression (p = 0.02). Ethanol intake was non-significantly inversely associated with ER-alpha expression (p = 0.07).Conclusions: Our findings suggest that the weak associations of diet with breast cancer risk could be explained, to some extent, by effects of diet on receptor expression in the normal mammary gland. [ABSTRACT FROM AUTHOR]

The authors analyzed data from two multistate, population-based case-control studies to investigate the association between age at any full-term pregnancy (FP) and breast cancer risk. Study subjects included breast cancer cases aged 20–79 years identified from four statewide cancer registries and randomly selected controls interviewed from 1988 to 1996. Complete information on a comprehensive set of risk factors for breast cancer was available for 9,891 cases and 12,271 controls. The large number of subjects enabled simultaneous adjustment of the covariates and efficient application of various modeling approaches. Overall, each 5-year increase in age at first FP was associated with an odds ratio of 1.07 (95% confidence interval (CI): 1.01, 1.13) for breast cancer. The corresponding estimates were odds ratio = 1.02 (95% CI: 1.00, 1.05) for age at second through ninth FPs. For age at last FP, the effect estimate (odds ratio = 1.01, 95% CI: 0.97, 1.06) was indistinguishable from that for other FPs after the first. In this analysis, a modest and transient increase in breast cancer risk after childbirth was also observed. The relatively greater effect of age at first FP is consistent with the existence of a long-term effect of early first FP on the differentiation of mammary cells, causing them to become less susceptible to carcinogenesis. Am J Epidemiol 2000;151:715–22. [ABSTRACT FROM PUBLISHER]

Objective: Pregnancies reduce the risk of ovarian cancer, and among multiparous women, levels of circulating progesterone might be higher during pregnancies with wider birth spacing. We hypothesized that childbirth with wider birth spacing might reduce maternal risk of invasive epithelial ovarian cancer more than births with narrower spacing.Methods: We conducted a case-control study nested in a nationwide cohort of Swedish women from 1961 to 2001. We selected five individually age-matched controls for each case of invasive epithelial ovarian cancer, and analysis for the effect of birth spacing was performed for 5,341 cases and 29,047 controls. We applied unconditional logistic regression analyses adjusting for age, ages at childbirth, educational level, area of residence, and gender of offspring.Results: Relative risk of invasive epithelial ovarian cancer associated with each one-year increase in average birth spacing is 1.00 (95% CI = 0.98-1.01) among all women and 0.99 (0.98-1.01) among those born before 1935 and less likely to have used oral contraceptives. Further analyses on the biparous and triparous women did not find a consistent association between birth spacing and the risk of ovarian cancer.Conclusions: Birth spacing is unlikely to be a major determinant underlying the protective effects of childbirth on ovarian cancer risk. [ABSTRACT FROM AUTHOR]

Risk factors for breast cancer-documented by intensive epidemiological investigations and viewed in the context of general principles of carcinogenesis-can be integrated to an etiologic model comprising 3 principal components: the likelihood of breast cancer occurrence depends on the number of mammary tissue-specific stem cells, which is determined in early life; all growth-enhancing mammotropic hormones affect the rate of expansion of initiated clones; and while a pregnancy stimulates the replication of already initiated cells, it conveys long-term protection through differentiation of mammary tissue-specific stem cells. This perspective accommodates much of what is known about the epidemiology and natural history of breast cancer and highlights the role of early life in the origin of this cancer. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Birth weight has been positively associated with breast cancer risk in adult life and is positively associated with the principal pregnancy estrogen estriol. Birth weight is lower among Chinese women than among Caucasian women, but paradoxically, pregnancy estriol levels are higher among the former than the latter. We studied a cohort of 317 Caucasian pregnant women in Boston, MA, and 339 Chinese pregnant women in Shanghai, China. We investigated whether maternal height, which is inversely associated with pregnancy estriol levels, interacts with this hormone in relation to birth weight, thus accommodating the apparently contradictory ecologic and analytic evidence concerning the role of pregnancy estrogens on breast cancer risk in the offspring. In both Boston and Shanghai, there was a positive association of pregnancy estriol with birth weight among taller women, whereas among shorter women the association was essentially null. The relevant interaction terms were highly significant in Boston ( p ≈ 0.006), whereas in Shanghai, where pregnant women were generally shorter, the interaction term was suggestive ( p ≈ 0.14). We conclude that maternal height should be considered an important risk factor for breast cancer in the offspring since it is a crucial determinant of birth weight, both directly and through positive interaction with the principal pregnancy estrogen estriol. © 2005 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Background There exists very little information on possible effects on birth size of micronutrient intakes at levels that are usually encountered among pregnant women in developed countries. Aim of the study To examine the relation of the intake of 20 micronutrients with birth weight, placental weight, birth length and head circumference of the offspring. Methods In a cohort of 222 Caucasian women with singleton pregnancies in Boston, USA, diet during pregnancy was ascertained at the 27th gestational week through a validated semi-quantitative food frequency questionnaire, covering also intake of dietary supplements. Micronutrient intakes were correlated with birth size parameters after adjustment for confounding variables, including total energy intake. Results Pantothenic acid, sodium and vitamin E were positively associated with all four birth size parameters. For pantothenic acid the association was statistically significant with respect to birth length, whereas for sodium with respect to head circumference and for vitamin E with respect to birth weight. In contrast, zinc was inversely associated with all four birth size parameters and the association was statistically significant with respect to head circumference. Conclusions In a moderately sized prospective study, we found evidence that pregnancy intake of pantothenic acid, vitamin E and sodium may be positively related with at least one of the studied birth size parameters, whereas an inverse association was found with respect to zinc intake. For the remaining 16 micronutrients, our findings indicate that they are not associated with birth size, at least within the range of intake encountered in this investigation. The results of this exploratory analysis need to be confirmed before patho-physiologic interpretations and generalizations are attempted. [ABSTRACT FROM AUTHOR]

For diseases with an infectious etiology, birth order may dictate the age of exposure to childhood infection, while sibship size may be a proxy for the probability of exposure. The authors examined whether birth order, sibship size, and childhood housing density affect risk of tooth loss and periodontal disease. The study included 28,690 adults aged ≥42 years who were participating in a 1998–2002 follow-up of persons listed in the Swedish Twin Registry. Logistic regression was used to calculate odds ratios and 95% confidence intervals, with adjustment for age, sex, education, and smoking and mutual adjustment for family composition (sibship size and/or birth order). Tooth loss and periodontal disease affected 8% and 19% of the twins, respectively. Each additional sibling increased the odds of tooth loss by 10% (95% confidence interval (CI): 1.06, 1.15) and the odds of periodontal disease by 5% (95% CI: 1.02, 1.08). Later birth order was associated with lower odds of periodontal disease. Each additional person per room in the childhood home increased the odds of tooth loss (odds ratio = 1.28, 95% CI: 1.03, 1.60) but lowered the odds of periodontal disease (odds ratio = 0.65, 95% CI: 0.48, 0.89). These findings are compatible with the hypotheses that adult oral diseases are associated with the probability of exposure in childhood and that earlier age at exposure lowers risk. [ABSTRACT FROM AUTHOR]

Objective: Because birth weight has been positively associated with adult life breast cancer risk and pregnancy estrogens have been hypothesized to affect breast cancer risk in the offspring, we have evaluated the association of pregnancy estriol (E3), estradiol (E2), progesterone and prolactin in maternal serum samples collected during the 16th and 27th gestational week with birth size parameters.Methods: Prospective study of 230 Caucasian women who delivered a live singleton after 37-42 weeks of gestation.Results: E3 at the 27th gestational week was significantly positively associated with birth weight, birth length and placental weight. Progesterone at the 27th gestational week was also significantly positively associated with birth weight and placental weight but, after mutual adjustment among the studied pregnancy hormones, these associations weakened considerably. There was also inconsistent evidence that SHBG and prolactin at the 27th gestational week may be respectively positively and inversely related with birth size parameters. Measurements during the 16th gestational week were generally unrelated to birth size parameters.Conclusions: Because E3 is a dominant estrogen during pregnancy, the positive association of it with birth weight allows the use of the latter as a proxy of in utero exposure to estrogens in breast cancer investigations. [ABSTRACT FROM AUTHOR]

Objectives: In a population-based case-control study in Yangzhong, China, we investigated the relationship between genetic polymorphisms of GSTP1 and susceptibility to gastric cancer and its premalignant lesion, chronic gastritis. The possible gene-gene interactions between GSTP1 polymorphisms and GSTM1, GSTT1 genes were explored.Methods: Epidemiologic data were collected by standard questionnaire from 133 gastric cancer cases, 166 chronic gastritis cases, and 433 cancer-free population controls. Blood samples for Helicobacter pylori and molecular marker assays were collected from 84 gastric cancer cases, 146 chronic gastritis, and 429 population controls. GSTP1 polymorphisms were determined by the PCR-RFLP method and H. pylori infection was measured by the ELISA method. Associations between certain GSTP1 genotypes and both gastric cancer and chronic gastritis were assessed by odds ratios (ORs) and 95% confidence intervals (CIs) derived from logistic regression.Results: The distributions of three GSTP1 genotypes, Ile/Ile, Ile/Val, and Val/Val, were similar in gastric cancer cases, chronic gastritis, and controls. After adjusting for age, gender, education, body mass index, pack-year of smoking, alcohol drinking, H. pylori infection, salt and fruit intakes, the adjusted ORs of Val/Val were 1.3 (95% CI: 0.1-11.2) for gastric cancer and 0.9 (95% CI: 0.2-4.8) for chronic gastritis. Combining the Val alleles (Val/Val and Ile/Val) into one group, no association was observed between GSTP1 and both gastric cancer and chronic gastritis. In addition, the allelism at the GSTP1 locus did not increase gastric cancer and chronic gastritis risks associated with the GSTM1 or GSTT1 genotypes.Conclusion: Our data suggest that the GSTP1 genotype seems not to be associated with the risk of gastric cancer and chronic gastritis in a high-risk Chinese population. [ABSTRACT FROM AUTHOR]

Umbilical cord blood is an alternative stem cell source for patients without matched family donors. In this study, we examined several parameters that have not been studied in detail – radiation dose, cell dose, age of mice, and maternal and neonatal characteristics of the cord blood donor – that affect engraftment of cord blood in non-obese diabetic–severe combined immunodeficient (NOD–scid) mice. Engraftment, measured using flow cytometry analyses of human CD45+ cells, was highest in 400 cGy-treated mice. Successful engraftment was demonstrated up to 6 months, with a mean engraftment of 31% (range 0–67%) of human cells in recipient bone marrow. Engraftment was skewed to B lymphocytes. The radiation dose of 350 cGy resulted in superior survival of the murine recipients compared with 400 cGy (P = 0.03). The sex of the NOD–scid recipients had a significant effect on survival (female superior to male, P = 0·01), but not on engraftment. There were high levels of variability among different cord units and among animals injected with the same cord unit. This variability may limit the clinical usefulness of the NOD–scid mice as hosts for the quantification of human stem cells. [ABSTRACT FROM AUTHOR]

Umbilical cord blood transplantation is considered an alternative to traditional bone marrow transplantation for patients who do not have matched sibling donors. In this study, we examined the effects of ex vivo treatment of human cord blood cells with cytokine mixtures and assessed the ability of treated cells to engraft in NOD-scid mice. We incubated the cord blood with a four-factor cytokine mixture of interleukin (IL)-3, IL-6, IL-11 and stem cell factor, or with a two-factor cytokine mixture of thrombopoietin and flt-3. Incubation of cord blood for 48 h with either cytokine mixture did not affect progenitor cell number or proliferative potential as measured by the high proliferative potential (HPP) assay. Cytokine-treated cord blood injected into irradiated NOD-scid mice resulted in multilineage human engraftment. Overall, incubation with cytokines resulted in variable levels of engraftment with different cord blood samples. Incubation of cord blood with the four-factor cytokine mixture resulted in increased survival of irradiated NOD-scid recipients. These results demonstrate that short-term ex vivo treatment of human progenitor cells gives variable results on in vivo multipotential capabilities. [ABSTRACT FROM AUTHOR]

Background: Leptin, the adipocyte-secreted protein product of the ob gene, has been strongly linked to obesity and is believed to play a role in the regulation of the reproductive system. This study examines the potential influence of lifestyle and dietary factors, as well as of other hormones, on serum levels of leptin. Methods: The authors studied a population of 48 healthy elderly Greek men. Sera from these men were analyzed for leptin, several steroid hormones, sex hormone-binding globulin, and insulin-like growth factor 1. The authors also utilized data from food frequency questionnaires and information on demographic, anthropometric, and lifestyle (cigarette smoking, alcohol and coffee drinking) factors. Results: Using linear regression modeling, serum leptin levels were inversely associated with testosterone and positively associated with estradiol and dehydroepiandrosterone sulfate, after adjustment for the other hormones and body mass index (BMI). Leptin levels in men with a BMI >30 kg/m[sup 2] were 170% higher than in men with a BMI <27 kg/m[sup 2] (95% CI 63– 346%). Height was also positively associated with leptin, independent of BMI. No notable relationships were observed between leptin, on the one hand, and smoking, alcohol drinking, coffee drinking, or total energy intake, on the other. When total energy intake was separated into its three major components (carbohydrate, fat, and protein), it appeared that fat intake may have an isocalorically differential effect on serum leptin levels; one marginal quintile increase in fat intake corresponded to an 11% increase in leptin (95% CI 0–24%). Conclusion: Serum levels of leptin may be influenced by other endocrine factors, especially testosterone and estradiol, and may be positively associated with excess fat intake independently of obesity. [ABSTRACT FROM AUTHOR]

Objectives: Several studies have found an inverse association between older age at last birth and endometrial cancer risk. A nested case-control study was undertaken to examine the influence of this and other aspects of reproductive patterns on the risk of developing endometrial cancer.Methods: Among women born in 1925 and later, 4,839 eligible patients were identified in the Swedish Cancer Register. For each case, five individually age-matched controls were randomly selected from a population-based Fertility Register. Relative risks were estimated from odds ratios obtained from conditional logistic regression analyses.Results: Compared to uniparous women, childless women were at a higher risk of endometrial cancer (odds ratio [OR] = 1.38, 95% confidence interval [CI] = 1.25-1.52). This association was stronger in younger (< 50 years) than in older (50+ years) women. At all ages of first birth, a delivery was associated with a reduced risk of endometrial cancer that slowly diminished with time. Among parous women, the risk decreased by almost 20% for each additional live birth (OR = 0.81, CI = 0.78-0.84). In an analysis limited to women with two or more births that compared the independent effects of age at first and at last birth, only older age at last birth was associated with a lowered risk of endometrial cancer. The risk decreased at a rate of about 15% per five-year delay of last birth.Conclusions: Endometrial cancer is often referred to as the prototype hormonally-determined disease in women. However, our findings give further support to the hypothesis that a birth may not only affect risk through hormonal influences, but possibly also through mechanical shedding of cells that have undergone malignant transformation. [ABSTRACT FROM AUTHOR]