BMC Cancer 2008, 8:36 http://www.biomedcentral.com/1471-2407/8/36 Table 5: Correlations between biomarker positivity for all lesions (case and control) COX-2 ER PR Cyclin-D HER2/neu P53 PPARγ COX2 ER PR Cyclin D HER-2/neu P53 P21 PPARγ -.310* .096 -.062 .092 -.102 .010 -.006 -.035 -.0667 -.104 .183 .142 -.036 .673*** .318** -.164 .206* .256* Spearman correlations .* less than 0.05 ** less than 0.005 ***less than .0005 sis. The use of aromatase inhibitors may be particularly useful in these patients given the evidence that aromatase expression is upregulated by prostaglandins, and aro- matase mRNA expression is suppressed by COX-2 inhibi- tors[38]. Several studies have identified younger age as a factor that increases the risk of recurrence after BCT for DCIS[39,40]; we attempted to determine if this was explained by higher COX-2 expression in younger women, but did not find an association between age and COX-2 expression, in agree- ment with previous studies[31]. We also examined the association between COX-2 expression and HER-2/neu over-expression. In invasive cancers, COX-2 expression is more often found in those patients who are HER-2/neu positive[41], but in a separate study of women with node negative breast cancer, the prognostic value of COX-2 pos- itivity was independent of HER-2/neu amplification[42]. We found a similar pattern in DCIS, in agreement with a recent study[18]; however, we did not note an increased risk of recurrence with co-expression of HER-2/neu and COX-2 over patients who expressed COX-2 alone. As far as we know this is the first report of PPARγ expres- sion in human DCIS, although one previous study does show a favorable effect of PPARγ positivity on prognosis in women with invasive ductal cancer[26]. PPARγs are members of the nuclear receptor super-family that includes steroid, retinoid and thyroid hormone recep- tors[43,44]. There are three isoforms: PPARα, PPARδ and PPARγ, which are encoded by different genes and demon- strate organ-specific variation in expression throughout the body. Two forms of PPARγ (PPARγ1and PPARγ2) have been identified. PPARγ2 is expressed only in fat cells; PPARγ1 has been found to be expressed in normal breast epithelium and breast cancers[45]. PPARγ as well as the other PPARs hetrodimerize with the retinoid X receptors (RXRs) and then bind to the peroxisome proliferator response elements (PPREs) in the promoter regions of tar- get genes. Ligand binding causes a conformational change .497*** -.389** .163 .414*** -.089 .233* .488*** .194 .123 .391*** in the heterodimer that causes the co-repressor protein to dissociate allowing for activation of gene transcription that is responsible for cell cycle modulation, cellular dif- ferentiation, decreased proliferation, and inhibition of angiogenesis[21,22]. Natural low affinity ligands of PPARγ include fatty acids and ecosanoids such as prostag- landin J2 (PGJ2). Thiazolidinediones, an FDA approved class of anti-diabetic drugs, are highly selective activating ligands for PPARγ at doses used to treat diabetes[46,47]. Our study suggests that the presence of PPARγ in DCIS may be protective against ipsilateral recurrence particu- larly in Grade 2 and 3 lesions. However, because of the higher rate of Grade 1 core loss during processing, PPARγ positivity was determined in only 9 of the 18 grade 1 DCIS lesions in the study. All nine of these grade 1 DCIS lesions were negative for PPARγ; six of these tumors were in the control group. It is possible therefore (and even likely, given the association of PPARγ expression with Grade 1 in invasive breast cancer[48]) that PPARγ expression in Grade 1 DCIS is more frequent than what we see in our population, but this awaits a larger study, and may require the use of whole sections rather than TMAs, As with COX- 2 positivity, there was no association of PPARγ positivity with age or HER-2 status, although it has been reported in one study that PPARγ may inhibit HER-2 pathways in cell culture models[49]. Previous studies have shown that PPARγ ligands were able to cause terminal differentiation of liposarcoma[50]. In breast cancer, numerous cell culture models have shown PPARγ ligand activation induces differentiation and inhibits proliferation[45,51]. Only one study to date has looked at PPARγ ligands in human breast cancer. It was undertaken in a group of women with refractory breast cancer. No response was seen after treatment[46]; how- ever, the authors did not examine tumors for PPARγ expression, and if this is associated with a favorable phe- notype, it is possible that these women with refractory advanced disease had largely PPARγ negative tumors. Page 7 of 11 (page number not for citation purposes)