Elevated levels of p27, p21 and cyclin D1 correlate with positive oestrogen and progesterone receptor status in node-negative breast carcinoma patients

Abstract

The search for better prognostic indicators and new treatment modalities in node-negative breast carcinoma patients is important. The aim of this study was to determine the immunohistochemical expression of central cell regulator proteins in relation to hormone receptor status, tumour-cell differentiation and prognosis. We investigated the immunoreactivity of p27, p21, cdk4, cyclin D1 and p53 in 77 node-negative breast carcinomas, with long-term follow-up (mean 163 months; range 20-227). Nuclear staining for p27 was seen in 87% of the carcinomas, for cdk4 in 92%, for p21 in 68%, for cyclin D1 in 58% and for p53 in 18%. Oestrogen receptor (ER) and progesterone receptor (PgR) nuclear staining was seen in 69% and 65% of the tumours, respectively. No correlation between the levels of p21 and p53 was observed. p21 overexpression was, however, associated with positive ER status. Elevated levels of p27 and cyclin D1 correlated with positive hormone status (both ER and PgR). We did find a significant correlation between p27 and cyclin D1 and histological grade of the tumours, with extensive positive immunostaining of p27 and cyclin D1 in well-differentiated carcinomas. The only significant prognostic factor in our series was histological grading. Ten-year relapse-free survival was significantly prolonged in patients with histological grade I tumours versus histological grade II and III tumours. Our results suggest that the expression of p27 and cyclin D1 is closely linked to hormone receptor status in breast carcinomas and to tumour differentiation, a finding that may be of importance in the treatment of hormone-dependent tumours.

Hormone receptors and proliferation in breast carcinomas of equivalent histologic grades in pre‐ and postmenopausal women

“…However, in the node-negative subgroup of these cases (n ϭ 249), a high p27 Kip1 expression indicated a poor prognosis. In contradiction to this, Reed et al 91 did not find p27 Kip1 to be a significant prognostic indicator in 77 node-negative breast carcinomas with a median follow-up of 13 years. In a study confined to grade 1 infiltrating ductal carcinomas (148 cases) with a median follow-up of 11.3 years, Leong et al 90 determined that p27 Kip1 was insufficiently sensitive to predict those patients with a poor outcome, a relatively small number of 19%.…”

“…Others have reported a lack of correlation between p27 Kip1 and proliferation. 55,56,90,91 These findings suggest that other proliferative factors, such as cyclin D1, 58,92 cyclin E 93 or c-myc, 94 may work to overcome the inhibitory effects of p27 Kip1 to allow cell proliferation, especially in postmenopausal women. We, as have others, 31,55,57,58,90,91 have observed a significant positive correlation between ER and PR and p27 Kip1 .…”

Stable ‘portrait’ of breast tumors during progression: data from biology, pathology and genetics

“…Proliferation markers KI-67 and topoisomerase II alpha levels were also positively correlated to ER-negative status (Molino et al 1997, Rudolph et al 1999b. Regarding cyclins, while cyclin E was associated with the absence of ER, the inverse was observed for cyclin D1 (Nielsen et al 1997, Barnes & Gillett 1998, Reed et al 1999, Spyratos et al 2000, Park et al 2001, Loden et al 2002. The level of the cyclin-dependent kinases inhibitors 1A (P21 WAF1/CIP1 ) and 1B (P27…”

“…) was found to be higher in ER-positive tumors (Barbareschi 1999, Reed et al 1999, Barbareschi et al 2000, Oh et al 2001.…”

“…Regarding cyclins, while cyclin E has been associated with high-grade tumors, the inverse was observed for cyclin D1 (Loden et al 2002). The level of P21 WAF1/CIP1 and P27 KIP1 was found to be higher in low-grade or welldifferentiated tumors (Barbareschi 1999, Reed et al 1999, Wu et al 1999, Oh et al 2001, Barbareschi et al 2000.…”