Spotlight

Abstract

Contardi et al., pp. 538–550 For several years, the cell surface molecule cytotoxic T-lymphocyte antigen-4 (CTLA-4), which is expressed on activated T cells, has been acknowledged as an important player in down-regulating T-cell responses. Although CTLA-4 is also expressed on nonlymphoid cells and a variety of leukemia cells, its expression on solid tumors to date has not been determined. To address this issue, Contardi and colleagues examined 34 human cell lines derived from various human solid tumors. The vast majority—78%—of these cells lines demonstrated cell surface expression of CTLA-4 as detected by flow cytometry. Approximately two thirds of these cells also expressed the CTLA-4 ligand, CD86. CTLA-4 expression was also not restricted to the cell lines; immunohistochemistry showed that malignant cells from tumor tissue samples from both osteosarcoma (n = 6) and ductal breast carcinoma (n = 5) patients stained positively for CTLA-4. Intriguingly, the authors demonstrated that CTLA-4 is functional on the tumor cells: incubation of the cell lines with ligands CD86 or CD80 induced apoptosis. This effect could be specifically blocked and was mediated through caspase-8 and caspase-3 activation. These results highlight a mechanism where constitutive expression of the surface molecule, CTLA-4, on solid tumor cells, could be potentially exploited to induce tumor cell apoptosis in a therapeutic context. Leo et al., pp. 561–568 Although antiestrogen therapy is an effective treatment in hormone-dependent breast cancer, the role of progesterone in breast cancer development is unclear. To date, data from experiments examining the effects of progesterone on breast cell lines are ambiguous and appear to be dependent on whether the cells express both the estrogen receptor (ER) and the progesterone receptor (PR) or only express PR. The authors of this report had previously shown that when the ER- and PR-negative breast cancer cell line MDA-MB-231 was transfected with PR, progesterone could inhibit cell growth both in vitro and in vivo. Here, using the same PR transfected cells, they conducted an extensive analysis of gene expression following progesterone treatment. Using microarray analysis, 151 genes showed differential expression that was greater than 3-fold. Intriguingly, 40 out of 43 genes that are involved in DNA replication, cell cycle progression and mitosis were down-regulated by at least 2-fold following progesterone treatment. Curiously, progesterone also decreased expression levels of 7 DNA repair genes, which the authors hypothesize may indicate imminent cell cycle arrest and apoptosis. The data give no clear-cut answers, but strongly indicate that progesterone can have profound antineoplastic and antiproliferative effects. These results are relevant to hormone-independent breast cancer, cancer phenotypes that lack ER and PR expression. In this context, progesterone treatment could induce anticancer effects when PR expression is reactivated with gene therapy, or in patients with an ER-negative PR-positive breast cancer phenotype. Wirtenberger et al., pp. 638–642 Allen-Brady et al., pp. 655–661 Family history is an established risk factor for breast cancer. Two reports in this issue shed light on important risk factors associated with familial breast cancer. In the first report, Wirtenberger et al., use a case-controlled study to examine whether having a rare polymorphism of the transcription factor c-MYC, c-MYC Asn11Ser, increases the risk of developing breast cancer. Genotyping patients from Polish (n = 349) and German (n = 356) BRCA1/2-negative study populations demonstrated that the presence of the c-MYC Asn11Ser polymorphism is associated with a 54% increased risk of developing breast cancer [Odds Ratio (OR) = 1.54, 95% CI 1.05–2.26, p=0.028]. This risk increased to OR=2.24 in patients over the age of 50. As c-MYC is activated in 70% of human cancers, these results highlight the c-MYC Asn11Ser polymorphism may also be a significant risk factors in other cancers and thus is worthy of further investigation. In the second report, Allen-Brady and colleagues investigate whether the breast cancer morphological subtype lobular breast cancer (LOB) is a risk factor for familial disease. Using the excellent resources of the Utah Population Database—that include genealogical data from at least 3 generations—and the Utah Cancer Registry, the authors show that relatives of LOB patients have an increased familial relative risk (FFR) of 4.51 (95% CI =2.79–6.89) of developing lobular cancer and increased FFR of 2.47 for developing any breast cancer. Surprisingly, these risks are higher than the FFR for first-degree relatives of patients with early onset of any breast cancer (which is considered to be a high risk factor). The results of this study strongly suggest that relatives of LOB patients are at high risk of developing breast cancer and thus should obtain rigorous screening.