The normal breast microenvironment of premenopausal women differentially influences the behavior of breast cancer cells in vitro and in vivo

<p>Abstract</p> <p>Background</p> <p>Breast cancer studies frequently focus on the role of the tumor microenvironment in the promotion of cancer; however, the influence of the normal breast microenvironment on cancer cells remains relatively unknown. To investigate the role of the normal breast microenvironment on breast cancer cell tumorigenicity, we examined whether extracellular matrix molecules (ECM) derived from premenopausal African-American (AA) or Caucasian-American (CAU) breast tissue would affect the tumorigenicity of cancer cells <it>in vitro </it>and <it>in vivo</it>. We chose these two populations because of the well documented predisposition of AA women to develop aggressive, highly metastatic breast cancer compared to CAU women.</p> <p>Methods</p> <p>The effects of primary breast fibroblasts on tumorigenicity were analyzed via real-time PCR arrays and mouse xenograft models. Whole breast ECM was isolated, analyzed via zymography, and its effects on breast cancer cell aggressiveness were tested <it>in vitro </it>via soft agar and invasion assays, and <it>in vivo </it>via xenograft models. Breast ECM and hormone metabolites were analyzed via mass spectrometry.</p> <p>Results</p> <p>Mouse mammary glands humanized with premenopausal CAU fibroblasts and injected with primary breast cancer cells developed significantly larger tumors compared to AA humanized glands. Examination of 164 ECM molecules and cytokines from CAU-derived fibroblasts demonstrated a differentially regulated set of ECM proteins and increased cytokine expression. Whole breast ECM was isolated; invasion and soft agar assays demonstrated that estrogen receptor (ER)^-, progesterone receptor (PR)/PR^-cells were significantly more aggressive when in contact with AA ECM, as were ER⁺/PR⁺cells with CAU ECM. Using zymography, protease activity was comparatively upregulated in CAU ECM. In xenograft models, CAU ECM significantly increased the tumorigenicity of ER⁺/PR⁺cells and enhanced metastases. Mass spectrometry analysis of ECM proteins showed that only 1,759 of approximately 8,000 identified were in common. In the AA dataset, proteins associated with breast cancer were primarily related to tumorigenesis/neoplasia, while CAU unique proteins were involved with growth/metastasis. Using a novel mass spectrometry method, 17 biologically active hormones were measured; estradiol, estriol and 2-methoxyestrone were significantly higher in CAU breast tissue.</p> <p>Conclusions</p> <p>This study details normal premenopausal breast tissue composition, delineates potential mechanisms for breast cancer development, and provides data for further investigation into the role of the microenvironment in cancer disparities.</p

Determinants of mortality in neonatal intestinal obstruction in Ile Ife, Nigeria

Background: Neonatal intestinal obstruction (NIO) is a common cause of mortality. This study determined the causes of mortality in patients with NIO at the Obafemi Awolowo University Teaching Hospitals Complex (OAUTHC), Ile Ife. Patients and Methods: Records of all cases of NIO managed at OAUTHC between January 1996 and December 2005 were retrospectively reviewed and the possible factors that may result in mortality were analysed. Results: Sixty-three neonates with intestinal obstruction were managed, representing 24.3% of the neonatal admissions during the study period. Forty-two were males and 21 were females (M:F = 2:1). The majority (71.4%) of the patients presented within the fi rst week of life. Anorectal malformation constituted 57.1% of the causes of NIO. Other causes included Hirschsprung's disease, duodenal atresia, intestinal malrotation with midgut volvulus and jejunal atresia. There were 18 deaths, with a mortality rate of 28.6%. Reoperation, postoperative bleeding and peroperative sepsis were signifi cant determinants of mortality. Conclusion: NIO is associated with signifi cant mortality in our centre. Repeat surgery, postoperative bleeding and sepsis were the signifi cant factors that contributed to mortality in NIO Keywords: Determinants, mortality, neonatal intestinal obstructionAfrican Journal of Paediatric Surgery Vol. 6 (1) 2009: pp. 11-1