Highlights of This Issue

Epithelial-mesenchymal transitions (EMT) and epithelial plasticity are postulated as mechanisms for cancer metastasis and dissemination but clinical evidence of these phenomena to date have largely been lacking. In this study, Armstrong and coworkers found evidence of the common expression of EMT biomarkers (N-cadherin, vimentin, O-cadherin, loss of E-cadherin) accompanied by stem cell marker (CD133) expression in circulating tumor cells (CTC) from men with metastatic castration-resistant prostate cancer and for common N-cadherin and vimentin expression in CTCs of women with metastatic breast cancer. These findings suggest the relevance of EMT to human cancer biology and that current epithelial-based methods of CTC isolation may miss cells that have undergone EMT.

In this study, Kais and colleagues applied an informatics approach to find genes that function in BRCA1- and BRCA2-regulated pathways, and candidates were tested in biologicalassays that are dependent on BRCA1 and BRCA2. They found that KIAA0101 powerfully controlled centrosome numbers. Changes in KIAA0101 abundance, by either depletion or overexpression, resulted in supernumerary centrosomes, suggesting that KIAA0101 protein levels must be precisely in balance to maintain the genome. Analyzing KIAA0101 in breast tumors showed a significant correlation between KIAA0101 overexpression in a tumor and the proliferation and aggressiveness of the breast cancer.

Phosphorylated histone H2AX (γH2AX) forms nuclear foci at sites of DNA damage and facilitates DNA damage response and repair. To identify microRNAs that modulate DNA damage response, Wang and colleagues developed a cell-based screening assay using ionizing radiation-induced γH2AX foci formation as a readout. MiR-138, a microRNA deregulated in some types of cancer, directly targeted H2AX 3′-UTR and reduced H2AX expression. Overexpression of miR-138 inhibited homologous recombination and enhanced cellular sensitivity to multiple DNA damaging agents, suggesting that miR-138 is an important regulator of genomic stability and a potential therapeutic agent to improve the efficacy of radiotherapy and chemotherapy.

Abnormalities in DNA methylation and associated tumor-suppressor gene silencing are common in breast cancer. This epigenetic gene silencing is mediated in part by methyl cytosine binding domain protein 2 (MBD2). Mian and colleagues showed that rapid, stable knockdown of MBD2 leads to de-repression of tumor suppressor genes, profound growth suppressionin culture, and a markedly decreased propensity for aggressive breast cancer cell lines to form in vivo xenograft tumors in mice. These findings show a role for MBD2 in breast cancer growth and progression and support the potential of MBD2 as a therapeutic target in aggressive breast cancers.