Malignant adrenocortical tumors are globally hypomethylated as compared with normal and benign tumors. Methylation profile differences may accurately distinguish between primary benign and malignant adrenocortical tumors. Several differentially methylated sites are associated with genes known to be dysregulated in malignant adrenocortical tumors.

Adrenocortical tumors are common and incidentally discovered in up to 14% of axial imaging studies performed for other indications. Most of these tumors are nonfunctioning but may require removal because of the risk of adrenocortical carcinoma. Unfortunately, most clinical and imaging features are still not accurate enough to allow definitive diagnosis and an increasing number of patients undergo adrenalectomy to exclude a cancer diagnosis. Adrenocortical carcinoma is an aggressive malignancy with no effective therapy for patients with locally advanced and metastatic disease. Studies using new genomic approaches including mRNA, miRNA, methylation, and CGH profiling have identified dysregulated genes and pathways that may have clinical implications in improved molecular diagnosis and prognostication of adrenocortical cancer (ACC). In this review, we highlight recent advances in the molecular diagnosis of adrenocortical tumors.

Treatment with the taxanes (Paclitaxel or Docetaxel) is often the therapy of choice for women with advanced breast cancer. In most cases, the taxanes can arrest cell proliferation at the G2/M phase and cause cell death. However, some tumors develop resistance during the course of treatment. Our preliminary gene expression microarray and western blot data of Bcl‐2, Caspase‐7, Bcl‐xL in our sensitive and resistant MDA‐MB‐231 cell lines showed remarkably little expression differences, suggesting that alternative non‐apoptotic cell death evasion pathways may be used to support the resistance phenotype. Our data also showed significant differential upregulation of cell cycle gene CDC25C (2‐fold; p=0.001), in Paclitaxel resistant vs. Docetaxel resistant cells, and increased expression of both CDK2 and Cyclin B (1.56‐fold; p=0.031 and 1.50‐fold; p=0.007, respectively). Our initial western blots of these proteins in our sensitive and resistant cell lines showed little difference, suggesting that resistant breast cancer cells may be able to overcome cell cycle arrest. From these preliminary data, we propose to further investigate different cell death pathways in MDA‐MB‐231 and MCF7 breast cancer cells. We also propose to determine what role specific cell cycle genes play in the resistant phenotype, and whether inhibiting these genes can reverse resistance. This research is funded by DOD Grant BC060777.

Treatment with the taxanes (Paclitaxel or Docetaxel) is often the therapy of choice for women with advanced breast cancer. In most cases, the taxanes can arrest cell proliferation at the G2/M phase and cause cell death. However, some tumors develop resistance during the course of treatment, which is a major concern for both patients and physicians. Several mechanisms have been proposed to explain how resistance to the taxanes occurs, but this phenomenon remains incompletely understood. We hypothesize that changes in cell death signaling, through apoptotic and non-apoptotic pathways, are responsible for taxane resistance in breast cancer. Using the MDA-MB-231 breast cancer cell line model, we selected cells that are resistant to either Docetaxel (DocR) or Paclitaxel (PacR). Subsequently we studied levels of cell death and the response to IC50 concentrations of these drugs. Given the molecular crosstalk that can occur between cells dying by apoptosis and the autophagy process, Western blots for prosurvival Bcl-2 and NFκB were performed, and these showed reduced expression in the taxane resistant cells compared to the sensitive cell lines. In conjunction with changes in apoptotic markers in the resistant cell lines, there were also changes in autophagy protein markers such as increased expression of cleaved LC3 and a decrease in p62/SQSTM1 expression, particularly in the PacR cells. Beclin-1 and XBP-1 expression, however, were not differentially expressed between the sensitive and both resistant cell lines. Beclin-1 and p62 have been implicated in the regulation of both Bcl-2 and NFκB expression. In order to determine whether the changes in autophagy marker protein expression was an indication of an alternative cell death process or cell survival, proliferation assays were performed with sensitive and resistant cells. Cells were counted after exposure for 7 days with and without 3-Methyladenine, an inhibitor of autophagosome formation. The addition of 3-MA significantly decreased cell number suggesting that autophagy may be a mechanism of cell survival in both taxane resistant models. Given our preliminary data, we propose to further investigate the role of autophagy and other alternative cell death evasion pathways seen in MDA-MB-231 taxane resistant and sensitive breast cancer cells. Our studies aim to improve the understanding of how different mechanisms of cell death evasion contribute to the resistance phenotype. Ultimately our studies may not only improve our understanding of taxane resistance at the bench, but may also provide the framework for formulation of novel therapies that may improve the success of taxane therapy in women with breast cancer in the clinic. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4857.