There is an increasing recognition that the mutations accompanying carcinogenesis may provide a window of therapeutic advantage designated synthetic lethality, an example of which is reported in this issue of the journal by Huang and colleagues (beginning on page 666). First discovered and studied in yeast, synthetic lethality has basic principles that have encouraged its development for treatment and now prevention in animal models of human cancer, especially malignancies refractory to standard approaches. The pros and cons of this approach and challenges in implementing it clinically are discussed. Cancer Prev Res; 4(5); 628–32. ©2011 AACR.

This perspective discusses the clinical trial reported by Burn and colleagues in this issue of the journal (beginning on page 655), which assessed aspirin and resistant starch for the prevention of colorectal adenomas in patients with familial adenomatous polyposis (FAP). The findings are examined in the context of previous clinical trials of aspirin in patients with sporadic adenomas and of sulindac or celecoxib in patients with FAP. This newly reported work raises important considerations of a role for aspirin in the clinical management of FAP patients and adds to considerations of a role for aspirin in the chemoprevention of colorectal cancer among broader populations. Cancer Prev Res; 4(5); 623–7. ©2011 AACR.

Mitochondria control essential cellular activities including generation of ATP via oxidative phosphorylation. Mitochondrial DNA (mtDNA) mutations in the regulatory D-loop region and somatic mtDNA mutations are common in primary human cancers. The biological impact of a given mutation may vary, depending on the nature of the mutation and the proportion of mutant mtDNAs carried by the cell. Identification of mtDNA mutations in precancerous lesions supports their early contribution to cell transformation and cancer progression. Introduction of mtDNA mutations in transformed cells has been associated with increased ROS production and tumor growth. Studies reveal that increased and altered mtDNA plays a role in the development of cancer but further work is required to establish the functional significance of specific mitochondrial mutations in cancer and disease progression. This review offers some insight into the extent of mtDNA mutations, their functional consequences in tumorigenesis, mitochondrial therapeutics, and future clinical application. Cancer Prev Res; 4(5); 638–54. ©2011 AACR.

Administration of estrogen replacement therapy (ERT) decreases the incidence of breast cancer, as shown in a double-blind, placebo-controlled randomized trial of the Women’s Health Initiative (WHI) in 10,739 postmenopausal women with a prior hysterectomy. Although paradoxical because estrogen is recognized to stimulate breast cancer growth, laboratory data support a mechanism of estrogen-induced apoptosis under the correct environmental circumstances. Long-term antiestrogen treatment or estrogen deprivation causes the eventual development and evolution of antihormone resistance. Cell populations emerge with a vulnerability, as estrogen is no longer a survival signal but is an apoptotic trigger. The antitumor effect of ERT in estrogen-deprived postmenopausal women is consistent with laboratory models. Cancer Prev Res; 4(5); 633–7. ©2011 AACR.

Lung cancer is the leading cause of cancer death in both men and women in the United States, with a low 5-year survival rate despite improved treatment strategies. These data underscore the great need for effective chemoprevention of this cancer. Mutations and activation of KRAS occur frequently in, and are thought to be a primary driver of the development of, non–small cell lung cancers (NSCLC) of the adenocarcinoma subtype. In this study, we developed a new approach for the chemoprevention of NSCLC involving specific targeting of apoptosis in mutant KRAS cells. This approach is based on a synthetic lethal interaction among TNF-related apoptosis-inducing ligand (TRAIL), the second mitochondria-derived activator of caspase Smac/DIABLO (Smac), and KRAS. Mutational activation of KRAS modulated the expression of TRAIL receptors by upregulating death receptors and downregulating decoy receptors. Furthermore, oncogenic KRAS repressed cellular FADD-like interleukin 1β–converting enzyme (FLICE)-like inhibitory protein (c-FLIP) expression through activation of Erk/mitogen-activated protein kinase (MAPK)-mediated activation of c-Myc. Smac overcame KRAS-induced cell-survival signaling by antagonizing X-linked inhibitor of apoptosis protein (XIAP). Therefore, the combination of TRAIL and a small molecule mimic of Smac induced apoptosis specifically in mutant KRAS cells without harming normal cells. We further showed that short-term, intermittent in vivo treatment with TRAIL and Smac mimic induced apoptosis in tumor cells and reduced tumor burden in a murine model of KRAS-induced lung cancer. These results reflect the potential benefit of a selective therapeutic approach for the chemoprevention of NSCLC. Cancer Prev Res; 4(5); 666–73. ©2011 AACR.