Identification of Functional Networks of Estrogen- and c-Myc-Responsive Genes and Their Relationship to Response to Tamoxifen Therapy in Breast Cancer

BACKGROUND: Estrogen is a pivotal regulator of cell proliferation in the normal breast and breast cancer. Endocrine therapies targeting the estrogen receptor are effective in breast cancer, but their success is limited by intrinsic and acquired resistance. METHODOLOGY/PRINCIPAL FINDINGS: With the goal of gaining mechanistic insights into estrogen action and endocrine resistance, we classified estrogen-regulated genes by function, and determined the relationship between functionally-related genesets and the response to tamoxifen in breast cancer patients. Estrogen-responsive genes were identified by transcript profiling of MCF-7 breast cancer cells. Pathway analysis based on functional annotation of these estrogen-regulated genes identified gene signatures with known or predicted roles in cell cycle control, cell growth (i.e. ribosome biogenesis and protein synthesis), cell death/survival signaling and transcriptional regulation. Since inducible expression of c-Myc in antiestrogen-arrested cells can recapitulate many of the effects of estrogen on molecular endpoints related to cell cycle progression, the estrogen-regulated genes that were also targets of c-Myc were identified using cells inducibly expressing c-Myc. Selected genes classified as estrogen and c-Myc targets displayed similar levels of regulation by estrogen and c-Myc and were not estrogen-regulated in the presence of siMyc. Genes regulated by c-Myc accounted for 50% of all acutely estrogen-regulated genes but comprised 85% (110/129 genes) in the cell growth signature. siRNA-mediated inhibition of c-Myc induction impaired estrogen regulation of ribosome biogenesis and protein synthesis, consistent with the prediction that estrogen regulates cell growth principally via c-Myc. The 'cell cycle', 'cell growth' and 'cell death' gene signatures each identified patients with an attenuated response in a cohort of 246 tamoxifen-treated patients. In multivariate analysis the cell death signature was predictive independent of the cell cycle and cell growth signatures. CONCLUSIONS/SIGNIFICANCE: These functionally-based gene signatures can stratify patients treated with tamoxifen into groups with differing outcome, and potentially identify distinct mechanisms of tamoxifen resistance

The global distribution and population at risk of malaria: past, present, and future

The aim of this review was to use geographic information systems in combination with historical maps to quantify the anthropogenic impact on the distribution of malaria in the 20th century. The nature of the cartographic record enabled global and regional patterns in the spatial limits of malaria to be investigated at six intervals between 1900 and 2002. Contemporaneous population surfaces also allowed changes in the numbers of people living in areas of malaria risk to be quantified. These data showed that during the past century, despite human activities reducing by half the land area supporting malaria, demographic changes resulted in a 2 billion increase in the total population exposed to malaria risk. Furthermore, stratifying the present day malaria extent by endemicity class and examining regional differences highlighted that nearly 1 billion people are exposed to hypoendemic and mesoendemic malaria in southeast Asia. We further concluded that some distortion in estimates of the regional distribution of malaria burden could have resulted from different methods used to calculate burden in Africa. Crude estimates of the national prevalence of Plasmodium falciparum infection based on endemicity maps corroborate these assertions. Finally, population projections for 2010 were used to investigate the potential effect of future demographic changes. These indicated that although population growth will not substantially change the regional distribution of people at malaria risk, around 400 million births will occur within the boundary of current distribution of malaria by 2010: the date by which the Roll Back Malaria initiative is challenged to halve the world's malaria burden