Tissue microarray analyses of G1/S-regulatory proteins in ductal carcinoma in situ of the breast indicate that low cyclin D1 is associated with local recurrence

Abstract

Ductal carcinoma in situ (DCIS) of the breast constitutes about 10% of all diagnosed breast cancers and, despite surgical removal, it may recur, either as DCIS or invasive breast cancer. Nuclear grade and growth pattern according to Andersen et al as well as surgical margins are factors that have been used to predict local recurrence, but ideally a set of tumour-specific factors should be identified and used as prognostic markers. Many cell cycle regulatory gene products have been shown to be involved in the formation of tumours and are either oncogenes or suppressor genes and involved in key processes in the transformation. We therefore characterised the cell cycle regulators cyclin E, cyclin D1, p27 and p16 in a material of DCIS cases arranged in a tissue microarray. With a manual tissue arrayer, 52% of the initial 177 DCIS samples were successfully targeted allowing immunohistochemical analyses of all four proteins in 92 cases of DCIS. As also observed in invasive breast cancer, there was a trend indicating that DCIS cases with high cyclin D1 were cyclin E low and oestrogen receptor-positive, whereas cyclin E high DCIS cases were cyclin D1 low and oestrogen receptor-negative. For the 64 patients that did not receive postoperative radiotherapy, there were 16 local recurrences (eight DCIS and eight invasive breast cancer) during a mean follow-up time of 63 months. Cyclin E, p27 or p16 were not associated with local recurrence, but interestingly cyclin D1 was significantly and inversely associated with local recurrence, both using univariate and multivariate analyses. In summary, using a tissue array approach we have shown that cyclin D1, besides growth pattern, is a prognostic marker for local recurrence in DCIS.

p53 Overexpression is a Predictor of Local Recurrence After Treatment for Both in situ and Invasive Ductal Carcinoma of the Breast

“…Turner et al have investigated the influence of cyclin D1 protein expression on breast cancer recurrence in a case-matched study in 49 patients and found that low levels of immunohistochemically detected cyclin D1 protein correlated with LR [29]. Also, in DCIS, low levels of cyclin D1 protein expression were associated with local recurrence [30]. As has been suggested before, these different findings from our study may be explained by different antibodies for cyclin D1 and methods of detection.…”

Tamoxifen Stimulates the Growth of Cyclin D1–Overexpressing Breast Cancer Cells by Promoting the Activation of Signal Transducer and Activator of Transcription 3

“…The beneficial effect of cyclin D1 overexpression on breast cancer survival was also reported by several others groups (15)(16)(17)(18)(19)(20). Notably, a study using microarray analysis of cyclin D1 expression reported that high cyclin D1 expression was associated with low risk of local recurrence of breast cancer, whereas low expression was associated with high risk (16).…”

“…Notably, a study using microarray analysis of cyclin D1 expression reported that high cyclin D1 expression was associated with low risk of local recurrence of breast cancer, whereas low expression was associated with high risk (16). The other studies showed that strong staining of cyclin D1 is associated with inverse tumor grade, smaller tumor size, and improved relapse-free and overall survival of breast cancer patients (18,20).…”

Cell Cycle Regulatory Proteins in Breast Cancer: Molecular Determinants of Drug Resistance and Targets for Anticancer Therapies

“…In addition to a positive correlation between cyclin D1 expression and aggressive cancers, as documented above, there is evidence to suggest otherwise as well. For example, a study using microarray analysis of cyclin D1 expression identified high cyclin D1 expression as a low risk factor for local recurrence of breast cancer (Jirstrom et al, 2003). Low expression of cyclin D1 expression was, conversely, associated with high risk of cancer recurrence.…”