The goal of CA90902 is to examine in umbilical cord blood samples the relation between measurements of stem cell potential and perinatal factors for breast cancer risk. The study is based on the hypothesis that cancer risk can be influenced in part by the hormonal environment in utero and that cancer risk is proportional to the number of primitive proliferating stem cells. In the previous grant cycle, we focused on the correlations between standard hematopoietic stem cell measurements and major endogenous hormones as well as birth weight. Building on the emerging results, we propose in this continuation application to explore further the relation between stem cell measurements and additional perinatal characteristics (preeclampsia, twin membership, and preterm birth) and endogenous hormones and growth factors (IGF-2) that have been found to be associated with breast cancer risk in adult life in epidemiologic studies or that might be relevant in prenatal origin hypothesis on breast cancer risk. Stem cell and growth factor measurements expand to include endothelial progenitor cells and angiogenic factors that might be related to intrauterine growth retardation. Umbilical cord blood from 240 donors with a wide range of maternal, gestational, and neonatal characteristics will be included. Stem cells include CD34+, CD34+/CD38-, CD34+/CD133+/VEGFR-2+ subpopulations, as well as colony-forming cells will be measured. Pro- and anti-angiogenic factors will be measured to assess angiogenic potential and to correlate with levels of endothelial progenitor cells and other study variables. We will apply regression analysis treating as outcome variables each measurement of stem cell potential and as predictor variables perinatal characteristics, hormones, and angiogenic factors.
A third aim will examine whether patients diagnosed with breast cancer (n=80) have higher measurements of stem cell potential than control subjects without breast cancer (n=80). It will also explore whether levels of hematopoietic stem cells in the breast cancer patients are correlated with CD44+/CD24- cells, a putative breast cancer stem cell, in their tumor tissue samples. The proposed study could contribute information on whether hormonal carcinogenesis process starts already early in the perinatal period and whether stem cell potential may be a common denominator for the effect of perinatal factors, providing a closer link between in utero exposure and risk of breast and other cancers. More speculatively, examining perinatal factors that include endogenous hormones and maternal, gestational, and neonatal characteristics might also potentially lead to future applications for early identification of high-risk individuals, perhaps through stem cell measurement, for potential cancer prevention measures.
Epidemiologic studies have provided evidence that in utero and perinatal events or conditions impact risk of breast and perhaps other cancers in the offspring. It has been difficult to directly study the pathogenic mechanisms involved in the sequences of events between early life exposures and adult life outcome. The proposed study could contribute information on whether the hormonal-influenced carcinogenesis process starts early in the perinatal period and whether stem cell potential may be viewed as a non-genetic indicator of host susceptibility, summarizing the effects of perinatal factors, and providing a closer link between in utero exposure and breast cancer risk. Examining perinatal risk factors that include endogenous hormones and maternal, gestational, and newborn characteristics might also potentially lead to future applications for early identification of high-risk individuals, through measurement of stem cell potential as a susceptibility marker summarizing the effect of a multitude of factors, for potential cancer surveillance and prevention measures. ? ? ? ?
