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BACKGROUND Mucinous tumors of the ovary have been thought to originate in two ways: by mullerian-type metaplasia of surface epithelium, and as monodermal teratomas. To gain a better understanding of their pathogenesis, the authors analyzed these tumors for their expression of estrogen receptors (ER) and progesterone receptors (PR) as markers of mullerian-type differentiation and for their content of gastric-type mucin as a marker of gastric differentiation. METHODS The histochemical expression of ER, PR, and gastric-type mucin was studied in 10 specimens of the cervix with normal endocervical glands (as a representative of mullerian-derived mucin-containing cells), 3 ovary specimens with surface epithelial inclusion cysts that contained endocervical-like mucin-containing cells (representing mullerian-type metaplasia), and 47 mucinous tumors of the ovary (29 benign, 8 with low malignant potential, and 10 malignant). RESULTS Normal endocervical glands expressed ER and PR and rarely expressed gastric-type mucin. Ovarian inclusion cysts showed strong expression of ER and PR in the cuboidal cells and drastically reduced expression in the endocervical-like mucin-containing cells. The cuboidal cells were negative for gastric-type mucin, but the endocervical-like mucin-containing cells expressed gastric-type mucin. Endocervical-like mucinous cells in benign and borderline mucinous tumors showed expression of PR and/or gastric-type mucin in all cases. CONCLUSIONS The staining results for the inclusion cysts support the thesis that the endocervical-like mucinous cells encountered in the ones that express ER and PR weakly or not at all and have histochemical properties of normal gastric epithelium have their origin in metaplasia of mullerian-type epithelium. Application of the same staining methods to benign ovarian tumors and those with low malignant potential suggests strongly that similar mullerian-type metaplasia is a major pathway in their pathogenesis. Cancer 1997; 80:908-16. © 1997 American Cancer Society.

BACKGROUND In the normal cell cycle, tumor suppressor gene products (p53) and cyclin (cyclin D1) cooperate. Abnormalities in the cooperation of these factors may result in malignant transformation of the cell. Mutant p53 protein overexpression is defined in many human cancers, including endometrial carcinoma. This study investigated the role of cyclin D1 in the development of human uterine endometrial carcinoma. METHODS Seventy-four patients whose pathology slides contained either normal or hyperplastic endometrium adjacent to endometrial carcinoma were studied. Immunohistochemical staining of the serial paraffin sections was performed using antibodies to p53 and cyclin D1. RESULTS The expression of cyclin D1 was restricted to only a few cells of normal and hyperplastic endometrium, whereas it was preferentially expressed in 40% (30/74) of endometrial carcinomas. The cells that overexpressed cyclin D1 also overexpressed p53. Moreover, all 30 cases with varied distributions of cyclin D1-positive cells corresponded identically with the distribution of p53-positive cells. Diffuse positivity for cyclin D1 was specifically observed in clinically advanced stages of pathologic G2 and G3 tumors. CONCLUSIONS The data suggest that coabnormal expression of cyclin D1 and p53 protein may contribute to the development of endometrial carcinoma and may also be involved in the progression to malignancy. Cancer 1996;78:1248-53.

BACKGROUND In the normal cell cycle, the appropriate interaction of factors such as tumor suppressor gene products (retinoblastoma susceptibility [Rb], p53) and cyclins is essential. Abnormalities in the interaction of these factors may result in malignant transformation of the cell. Malignant transformation of the endometrium, which is believed to be a sex steroid-dependent tumor, probably involves a process of uncoupling of these factors and sex steroid hormone receptors. This study is designed to test this hypothesis. METHODS Fifty-six patients whose pathology slides contained either normal or hyperplastic endometrium adjacent to endometrial carcinoma were selected. Immunohistochemical staining of serial paraffin sections was performed using antibodies to estrogen receptors (ER) and progesterone receptors (PR), p53, and Rb, as well as cyclin E. RESULTS The normal and hyperplastic endometria adjacent to carcinoma showed positive staining for ER and PR and negative staining for p53. Of 56 carcinomas, 39 (69.6%) showed homogeneous positive staining for ER and PR and negative staining for p53, whereas the remaining 17 carcinomas (30.4%) contained varied distributions of ER- and PR-negative cells, and p53-positive cells (6 were negative or focally positive for ER/PR and diffusely-positive for p53, 4 were regionally-positive for ER/PR and regionally-positive for p53, and 7 were diffusely positive for ER/PR and focally-positive for p53). The p53-positive cells corresponded to those that stained negatively for ER/PR. This topographic inverse relationship between ER/PR expression and p53 expression also correlated with the staining intensities. Furthermore, the cells with weak or negative staining for p53 had a tendency to stain positively for Rb and weakly positive for cyclin E, whereas the cancer cells with definite positivity for p53 tended to stain either weakly or negatively for Rb and definitely positive for cyclin E. The cells showing diffusely positive for p53 were present significantly in clinical Stage III and pathologic Grade G3. CONCLUSIONS In the development of endometrial carcinoma, stepwise abnormalities of sex steroid receptors, tumor suppressor gene products, and cyclins apparently exist, and may correlate with the progression of the malignant process. Cancer 1996;77:321-9.

BACKGROUND To examine the steroid hormone dependent growth mechanism of human endometrial hyperplasia and carcinoma, expression levels of steroid receptor cofactors, such as coactivators (steroid receptor coactivator 1 [SRC-1] and p300/cyclic AMP-response element-binding protein (p300/CBP]) and corepressors (nuclear receptor corepressor [NCoR] and silencing mediator for retinoid and thyroid-hormone receptors [SMRT]), were investigated. METHODS The expression levels of cofactors were examined immunohistochemically using 20 samples of normal endometria, 36 samples of hyperplastic endometria, and 58 of malignant endometria and were compared with the expression levels of estrogen receptor (ER), progesterone receptor (PR), and a proliferation marker, Ki-67. RESULTS In samples of normal endometria, the expression of coactivators was observed diffusely in glandular cells in the proliferative phase, with a mean positivity index (PI) of 81.8 for SRC-1 and 91.3 for p300/CBP, whereas expression levels decreased in endometrial hyperplasia (PI: SRC-1, 58.9; p300/CBP, 83.8) and endometrial carcinoma (PI: SRC-1, 45.0; p300/CBP, 55.4). In endometrial hyperplasia, there was a significant correlation between the expression of ER and SRC-1 or p300/CBP. In contrast, there were no significant statistical or topologic correlations between the expression of coactivators and the expression of ER/PR in endometrial carcinoma. The expression of corepressors generally was limited, except for elevated expression of NCoR in endometrial hyperplasia (PI, 23.8). CONCLUSIONS The current study showed that expression levels of the steroid receptor coactivators SRC-1 and p300/CBP were reduced in endometrial carcinoma compared with normal and hyperplastic endometrium. In addition, topologic coexpression of both coactivators and ER/PR was lost in endometrial carcinoma. Accordingly, limited response to sex steroids in patients with endometrial carcinoma may be ascribed to the dissociation of cofactors and ER/PR. Cancer 2003. © 2003 American Cancer Society.

BACKGROUND Abnormality of cell cycle regulators and tumor suppressors, such as cyclin dependent kinase inhibitors (cdkIs), has been reported in malignant tumors. The current study was undertaken to examine the involvement of a cdkI, p27Kip1 (p27), in the neoplastic process of the uterine cervical epithelium. METHODS Immunohistochemical staining of p27 was performed in samples of normal cervical tissue (30 samples), cervical intraepithelial neoplasias (CINs; 17 samples), and invasive squamous cell carcinoma (SCC; 25 samples). The results were compared with the expression levels of Ki-67, cdk2, and cyclin E. The functional aspects of the p27 protein, such as its ability to bind to cdk2 and the phosphorylation activity of p27-bound cdk2, also were evaluated with an immunoprecipitation and histone H1 kinase assay. RESULTS In normal cervical epithelia, the expression of p27 was strong in the intermediate and superficial cells but very weak in the parabasal cells. In CIN samples, the expression of p27 was negligible. The expression of p27 in these tissues showed an inverse topologic correlation to that of Ki-67, cdk2, and cyclin E. However, it is noteworthy that the number of p27 positive cells increased in SCC samples that also showed increased expression of Ki-67, cdk2, and cyclin E. The p27 protein in SCC samples was bound to cdk2 and cyclin E. However, cdk2 that was bound to p27 still possessed histone H1 kinase activity. CONCLUSIONS The expression of p27 may be involved in the growth regulation of the normal squamous epithelium in the uterine cervix. However, aberrant function of p27 expression may occur in invasive SCC of the cervix. Cancer 2001;92:3005–11. © 2001 American Cancer Society.

BACKGROUND The purpose of this study was to identify biologic differences between ovarian clear cell carcinoma and other ovarian adenocarcinomas by comparing the expression of cell cycle regulatory molecules and by analyzing the survival of the patients. METHODS In 51 cases of epithelial ovarian carcinoma, the expression of the cell proliferation marker Ki-67 and that of the cell cycle regulatory molecules p53, p16, p21, p27, cyclin E, and cyclin A was studied using immunohistochemical techniques. The correlations among clinical stage, histologic subtype, labeling index for Ki-67, and expression of these cell cycle regulators were examined statistically. Multivariate survival analysis was performed using these factors in the Cox proportional hazards model. RESULTS Clear cell carcinoma revealed such trends as low expression of both p53 and cyclin A and significantly increased expression of both p21 and cyclin E (compared with the other histologic subtypes). In all ovarian carcinomas, a very strong positive correlation (correlation coefficient 0.79; P < 0.0001) between p53 positive staining and cyclin A positive staining and a weak positive correlation (correlation coefficient 0.47; P < 0.01) between p21 positive staining and cyclin E positive staining were recognized at the level of expression of cell cycle regulatory molecules. Clinical stage was the only independent predictive factor for the survival of the patients. CONCLUSIONS Among ovarian adenocarcinomas, clear cell carcinoma exhibits a unique pattern of expression of cell cycle regulatory molecules, though in this study the survival of the patients did not correlate with histologic subtype, only with clinical stage. Cancer 1999;85:669–77. © 1999 American Cancer Society.

BACKGROUND Abnormalities in G1 cell cycle regulation have been associated with the malignant transformation of cells. To obtain further information about the role of factors regulating the G1 cell cycle in the development of endometrial carcinoma, the authors analyzed the expression of cdk4 (cyclin-dependent kinase) and p16INK4 (an inhibitor of cdk4). METHODS Immunohistochemical staining was performed on 20 specimens of normal endometria and 41 specimens of endometrioid-type endometrial carcinoma using antibodies against cdk4 and p16INK4. RESULTS In the glandular epithelia of the normal endometria, cytoplasmic staining of cdk4 and p16INK4 was observed only in the proliferative phase, but nuclear staining of these agents was negligible. In endometrial carcinomas, 8 (19.5%) and 14 (34.2%) were positive for cdk4 and p16INK4 in the nucleus, respectively. Topographically, the nuclear cdk4 positive tumor cells were negative for p16INK4 and the nuclear p16INK4 positive tumor cells were found in areas without nuclear cdk4 expression, suggesting an inverse correlation between the two agents. In addition, the poorly differentiated carcinomas were more frequently positive for nuclear cdk4 than were the highly differentiated carcinomas (P = 0.03). CONCLUSIONS These data suggest that increased expression of nuclear cdk4 associated with loss of p16INK4 expression could be involved in the carcinogenesis of a subset of endometrial carcinomas. Cancer 1997; 80:2250-6. © 1997 American Cancer Society.