ANTICANCER RESEARCH 24: 2185-2192 (2004)
Cyclin D1 Expression in Endometrioid-type Endometrial Adenocarcinoma is Correlated with Histological Grade and Proliferative Activity, but not with Prognosis Y. NISHIMURA1, J. WATANABE2, T. JOBO3, N. KATO1, T. FUJISAWA1, Y. KAMATA1 and H. KURAMOTO1 1Department
of Clinical Cytology, Graduate School of Medical Sciences, Sagamihara, Kanagawa; 2Department of Pathology and 3Department of Obstetrics and Gynecology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
Abstract. To elucidate carcinogenesis in the endometrium, we investigated cyclin D1 immunoreactivities in 20 normal endometria, 20 endometrial hyperplasias and 141 endometrioidtype endometrial adenocarcinoma. We also evaluated the correlation of cyclin D1 expression with Ki-67, cyclin E, cyclin A, cdk2, p27 and p53, and clinicopathological parameters and prognosis. Cyclin D1 expression increased significantly with histological grade, and the labeling index (LI) for cyclin D1 was 12.1±23.4% in G1, 12.7±23.7% in G2 and 15.7±18.5% in G3. The LIs were significantly correlated with those for cyclin E, cyclin A and Ki-67, but not with the LIs of cdk2, p27 or p53. In contrast, high cyclin D1 expression was significantly correlated with low p53 expression. Cyclin D1 expression was not significantly correlated with any of the clinicopathological parameters except histological grade. Cyclin D1 expression was significantly correlated with histological grade and proliferative activity, but not clinicopathological parameters and prognosis in endometrial adenocarcinoma. Cyclins are key components in the regulation of the cell cycle in combination with their respective cyclin-dependent kinases (cdks) (1). Cyclin D1 belongs to a family of three closely related D-type cyclins, cyclin D1, D2 and D3. These three proteins are expressed in proliferating cells in an overlapping and redundant fashion. D-cyclins selectively control cell cycle progression by activating their cdk partners, cdk4 and cdk6, which phosphorylate retinoblastoma (RB) protein and move the cell cycle into
Correspondence to: Hiroyuki Kuramoto, Department of Clinical Cytology, Graduate School of Medical Sciences, 1-15-1, Kitasato, Sagamihara, Kanagawa, 228-8555, Japan. Tel/Fax: +81-42-7789276, e-mail:
[email protected] Key Words: Cyclin D1, endometrial adenocarcinoma, cell cycle.
0250-7005/2004 $2.00+.40
the S-phase through the G1-phase (2). Mitogenic growth factors such as epidermal growth factor, basic fibroblast growth factor and insulin-like growth factor-I promote progress through the cell cycle by enhancing cyclin D-cdk4 and cyclin D-cdk6 complex formation and kinase activities during G1-phase (3,4). The relevance of cyclin D1 overexpression in breast cancer is emphasized by the finding that tissue-specific expression of cyclin D1 in transgenic mice results in mammary hyperplasia and adenocarcinoma (5). Moreover a prominent role for cyclin D1 in the growth of breast epithelia is observed (6) and cyclin D1 knockout mice show a marked defect in breast epithelial development during pregnancy (7). Cyclin D1 overexpression has been reported to be the worst prognostic factor in breast carcinoma (8), B-lymphocyte malignancy (9), hepatocellular (10) and esophageal carcinoma (11). On the other hand, in breast carcinoma, a positive correlation between cyclin D1-positivity and good clinical outcome is indicated (12,13). The reasons for the conflicting behavior of cyclin D1 are unclear. Endometrial carcinoma is one of the most common malignancies of the female genital tract (14). The most common histological type of this carcinoma is endometrioid adenocarcinoma, which accounts for 75-80% of all endometrial carcinomas. Endometrioid adenocarcinoma arises in a hyperestrogenic environment with previous or coincidental endometrial hyperplasia (15-17). Nikaido et al. (18) and Shih et al. (19) observed a significant association of cyclin D1 expression in endometrial carcinoma with histological grade, clinical stage and p53 expression. However, Ito et al. (20) studied the immunolocalization of cyclin D1, cyclin E, cdk4 and cdk2 in endometrial carcinoma of endometrioid type, showing that the labeling index for cyclin D1 was not significantly correlated with any parameters examined, including surgical stage and histological grade. Previous study on cyclin D1 expression
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ANTICANCER RESEARCH 24: 2185-2192 (2004) Table I. Correlation between cyclin D1 LI and clinicopathological parameters in endometrioid adenocarcinoma of the uterine corpus .
Clinicopathological parameters
No. of cases
Normal
No. of positive cases (%)
Cyclin D1 LI(%) (Mean±SD)
Secretory Proliferative
20 12 8
0(0.0%) 0(0.0%) 0(0.0%)
0.2±0.9 0.0±0.0 0.5±1.4
Simplex Complex Complex atypical
20 9 4 7
5(25.0%) 2(22.2%) 2(50.0%) 1(14.3%)
3.7±5.0 3.2±3.5 5.8±5.8 2.9±6.5
G1 G2 G3
141 78 34 29
Stage
FIGO I FIGO II FIGO III FIGO IV
Group
LVSI
#p=0.0274 ##p=0.0071 *
Hyperplasia
Adenocarcinoma Grade
P-value
**
*p=0.0394 **p=0.0249 ***p=0.0093 ****p=0.0018
65(46.1%) 31(39.7%) 14(41.2%) ## # 20(69.0%)
13.0±22.4 12.1±23.4 12.7±23.7 **** 15.7±18.5 ***
91 18 28 3
41(45.1%) 9(50.0%) 12(42.9%) 3(100%)
14.2±22.3 13.0±22.5 9.8±11.9 16.2±14.2
N.S.
1 2 3
64 54 18
28(43.8%) 25(46.3%) 9(50.0%)
12.8±21.6 14.7±26.5 8.1±9.8
N.S.
negative positive
92 36
37(40.2%) 21(58.3%)
13.6±23.4 14.0±22.5
N.S.
Myometrial invasion
