[Changing behavior of estrogen and progesterone receptors with metastasis or recurrence of breast cancer].

Changes in level of estrogen receptor (ER) and progesterone receptor (PgR) and their affecting factors were studied with metastasis or recurrence of breast cancer. Since 1983, from 177 patients, 443 specimens were obtained and 244 simultaneous and 122 sequential pairs were compared. The consistency rate was 81% for both ER and PgR with simultaneous comparison,and 69% for ER and 71% for PgR with sequential comparison, mainly due to positive-to-negative change, and less than 10% of negative-to-positive change. Positive-to-negative change was prominent with intervening endocrine treatment, and it was significant (p=0.015) for ER by multiple regression analysis of age, interval of sampling and from prior surgery, intervening chemotherapy, endocrine therapy and human epidermal growth factor receptor 2 (HER 2). Based on recent data of ER and PgR, feasible treatment seems to be planned, because about 30% of them are different from that of primary lesion.

Relationship between HPV typing and the status of G2 cell cycle regulators in cervical neoplasia.

We examined human papillomavirus (HPV) typing and the status of ATM, chk2, CDC25C, cdc2 and cyclinB1 in cervical intraepithelial neoplasia (CIN) and invasive cancer (IC). A total of 93 samples [normal: 10; CIN: 34 (CINI:9, CINII:12, CINIII:13); IC: 49 (stage I:10, stage II:21, stage III:15, stage IV:3)] were included in this study. HPV status was evaluated by the PCR non-radioactive HPV detection system. We analyzed ATM, chk2, CDC25C, cdc2 and cyclinB1 protein expression by immunohistochemistry. HPV DNA was detected in 73.5% of 34 CINs and 89.8% of 49 ICs. Detection of HPV subtypes 16 and 18 was more frequent in ICs (46.9%) than in CINs (23.5%) (p=0.0387). Abnormal expression of ATM, chk2, CDC25C, cdc2 and cyclinB1 were 2.9%, 32.4%, 2.9% 20.6% and 0% in CINs and 8.2%, 30.6%, 10.2%, 46.9% and 12.2% in ICs. The alteration of cdc2 was higher in ICs than in CINs (p=0.0198). Altered expression of cdc2 was higher in HPV16 and 18 cases (69.6%) than in other cases (26.9%) (p=0.0042). However, the relationship between HPV typing and ATM, chk2, CDC25C and cyclinB1 expression was not significant. Cdc2 is implicated in cervical carcinogenesis and may be related to p53 inactivation by HPV.

Relationship between HPV typing and abnormality of G1 cell cycle regulators in cervical neoplasm.

OBJECTIVE: In tumorigenesis, loss of function of the G1 pathway (p16-CDK4/cyclinD1-pRB pathway (RB pathway) and p14-MDM2-p53 pathway (p53 pathway)) is a theoretically essential event. The simultaneous analysis of all components of the RB and p53 pathway may be able to explain cervical tumorigenesis. However, there are no reports in which all components of the G1 pathway and HPV typing were examined simultaneously in cervical cancer. METHODS: We examined HPV typing and the status of the G1 pathways simultaneously by PCR-SSCP, multiplex PCR, methylation-specific PCR, and immunohistochemical techniques in cervical neoplasia. A total of 105 samples (normal, 10; cervical intraepithelial neoplasm (CIN), 42; invasive cancer (IC), 53) were included. RESULTS: Abnormality of the RB pathway tended to be more frequent in ICs (60.4%) than in CINs (31.0%) (P = 0.069). The primary target was p16 (CIN, 14.3%; IC, 43.4%; P = 0.032). Abnormality of the p53 pathway was detected in ICs (56.6%) and in CINs (40.5%) (P = 0.1494). In particular, strong expression of MDM2 was higher in ICs (32.1%) than in CINs (7.1%) (P = 0.0045). Abnormalities of the RB and p53 pathways were higher in low-risk and negative HPV than in high-risk HPV (81.3% vs 51.4%, P = 0.0657; 81.3% vs 45.9%, P = 0.0328). Seven HPV-negative cases had abnormalities in the RB or p53 pathways. CONCLUSION: In conclusion, abnormality of the G1 pathway may be one of the important mechanisms for carcinogenesis of low-risk and negative HPV cases.

Alteration of G2 cell cycle regulators occurs during carcinogenesis of the endometrium.

OBJECTIVES: In this study, we examined the alteration of the G2 pathway in endometrial hyperplasia (EH) and endometrioid-type endometrial cancer (EC), and analyzed the relationship between the G2 pathway status and the p53 pathway status. METHODS: A total of 103 cases (proliferative phase of the endometrium: 20, EH: 22, and endometrioid-type EC: 61 (I: 39, II: 5, III: 15, recurrence: 2)) were included in this study. We examined the ATM, chk2, CDC25C, cdc2, and cyclin B1 protein expression by immunohistochemistry. In 55 cases (EH: 15; EC: 40), we analyzed CHK2 mutations by RT-PCR-SSCP. RESULTS: There were no CHK2 mutations in endometrial disease. Elevated or reduced expression rates of ATM, chk2, CDC25C, cdc2 and cyclin B1 were 4.5% (1/22), 0%, 0%, 0% and 4.5% (1/22) in EH and 3.3% (2/61), 4.9% (3/61), 13.1% (8/61), 9.8% (6/61) and 9.8% (6/61) in EC. Alteration of the G2 pathway was higher in EC (32.8%; 20/61) than in EH (9.1%; 2/22; p = 0.047). The G2 pathway was significantly higher in the altered p53 pathway group (48.4%; 15/31) than in the normal p53 pathway group (16.7%; 5/30) in EC (p = 0.0134). The altered p53 pathway tended to be related with the cdc2/cyclin B1 status (p = 0.0529). CONCLUSIONS: Alteration of the G2 pathway is thought to occur during carcinogenesis of the endometrium.

Relationship between p53 pathway and estrogen receptor status in endometrioid-type endometrial cancer.

We analyzed the mechanism of estrogen receptor (ER) loss and status of the p53 pathway in 64 cases of endometrial cancer. 26.6% (17 of 64) of endometrial cancers lost ER. Methylation of the ER CpG island was significantly related to ER status (P = 0.0074). However, the methylation site of the ER CpG island differed between breast and endometrial cancers. The abnormal expression rate of p14ARF, MDM2, p53, and the p53 pathway were 7.8% (5 of 64), 32.8% (21 of 64), 25.0% (16 of 64) and 53.1% (34 of 64), respectively. There was no significant difference in the overexpression of MDM2 between p53-positive cases (43.8%: 7 of 16) and p53-negative cases (29.2%; 14 of 48) (P = 0.3595). Abnormal p53 was higher in grade 3 tumors (55.6%; 5 of 9) than in grade 1 and 2 tumors (20.0%; 11 of 55) (P = 0.0364). The abnormality of the p53 pathway was higher in grade 3 tumors (88.9%; 8 of 9) than in grade 1 and 2 tumors (47.3%; 26 of 55) (P = 0.0294). However, there was no significant difference in abnormal p53 pathway between ER-negative and ER-positive cases. In endometrial cancer, ER CpG island methylation was the important mechanism of ER loss. However, there was no significant relationship between the p53 pathway and ER status.