Aberrant expression of cyclin D1 is associated with poor prognosis in early stage cervical cancer of the uterus.

OBJECTIVE: Many investigators have studied the expression of G1 phase regulatory protein in uterine cervical cancer. However, it is unclear which step of the genetic expression participates in cyclin D1 expression and what its prognostic meaning is. The aims of this study were to evaluate the regulatory level of cyclin D1 expression and the relationship between the expression of cyclin D1 and its inhibitor, p21WAF1/CIP1, and to evaluate their impact on the prognosis of early stage cervical cancer. METHODS: The presence of cyclin D1 mRNA was studied using Northern blot in 6 normal cervices and 7 invasive cervical cancer specimens. Western blot was used to detect the cyclin D1 protein in 8 normal cervices and 8 invasive cancer specimens. Thirty-two cases of FIGO stage Ib-IIa cervical cancers (28 squamous cell carcinomas, 3 adenocarcinomas, 1 adenosquamous cell carcinoma), 31 cases of cervical intraepithelial neoplasia 3 (CIN 3), and 28 normal cervices were stained for cyclin D1 and p21(WAF1/CIP1) using monoclonal antibody. Statistical analysis was performed to assess the differences in expression and their prognostic significance. RESULTS. Cyclin D1 mRNA was found to be underexpressed in cervical cancer. Western blot also revealed underexpression of cyclin D1 protein in cervical cancer compared to normal controls. Positive immunohistochemical staining of cyclin D1 was noted in 28/28 (100%) of the normal controls, 1/31 (3%) cases of CIN 3, and 9/32 (28%) cases of invasive cancer. The number of positively stained specimens was lower than that of normal controls in CIN 3 and cervical cancer specimens (P = 0.005). Fifteen of 28 (54%) normal controls, 15/31 cases (48%) of CIN 3, and 27/32 cases (84%) of invasive cancer were proved positive for p21WAF1/CIP1 immunohistochemistry. p21WAF1/CIP1 was more highly expressed in cervical cancer than in that of either normal controls or CIN specimens (P = 0.001). Positive immunostaining of cyclin D1 and p21WAF1/CIP1 was not related to high-risk factors (pelvic lymph node metastasis, deep cervical stromal invasion, parametrial invasion, large tumor size, and unusual histologic type) and human papilloma virus infection. Positive cyclin D1 immunostaining was associated with decreased disease-free survival and a lower overall survival (P = 0.0175 and 0.0189, respectively). On multivariate analysis, positive cyclin D1 expression was a significant prognostic variable for recurrence (P = 0.0004). CONCLUSION: Underexpression of cyclin D1 was regulated at the level of transcription in cervical cancer. Although cyclin D1 was underexpressed in cervical neoplasias, it was more frequently expressed in malignant lesions. p21WAF1/CIP1 was more highly expressed in cervical cancers than in either normal cervices or CIN 3 specimens. Unfavorable prognoses were associated with cyclin D1 expression, and not with the expression of its inhibitor, p21WAF1/CIP1.We conclude that immunohistochemical assessment of cyclin D1 can be a useful molecular marker for predicting prognosis in early stage cervical cancer of the uterus.

Induction of c-Jun mRNA without changes of estrogen and progesterone receptor expression in myometrium during human labor.

To elucidate the endocrine mechanism of human parturition, the expression of c-Jun and c-Fos mRNA were examined in relation to estrogen receptor (ER) and progesterone receptor (PR) in human myometrium. c-Jun mRNA was detected in all myometrial tissues (n=5) during labor but not before labor (n=5) and in oxytocin-resistant postterm pregnancy (n=3). c-Fos mRNA was detected in only one myometrial tissue from a woman in labor. The distribution and intensity of immunostaining for ER and PR were semiquantitatively scored. During the late pregnancies, no significant difference was seen in the receptor scores for myometrial ER and PR between the patients who experienced labor and those who did not. Receptor scores for ER and PR were significantly lower in postterm pregnancy than in late pregnancy, regardless of the labor status. These data suggest that there are no changes in ER and PR in human myometrium during parturition. On the other hand, postterm pregnancy is associated with low ER and PR. c-Jun, induced during labor without changes in ER and PR, may play a role as a signaling mechanism in human myometrium.

Molecular genetics of gynecologic cancer.

During the past decades, the expansion of molecular biology has had a pivotal role in understanding the basis of cancer development and progression. In addition, real advances have been made in the application of DNA recombinant technology to cancer therapy and patient management. In gynecologic oncologic fields, there are also many investigations to explore the basic pathogenesis of gynecologic cancer, such as cervical cancer, ovarian cancer, and endometrial cancer. It is now known that specific types of human papilloma virus (HPV) are the principal etiologic agents for both cervical cancer and its precursors. However, the various kinds of alterations in oncogenes and tumor suppressor genes may play additional roles in carcinogenesis of cervical cancer. Although ovarian carcinoma is the most frequent cause of death from gynecologic malignancies, the histogenesis and biological characteristics of these tumors are not well understood. During the last several years, many key observations have been made concerning the genetic alterations associated with ovarian cancer. Recent researches including some dominant oncogenes and tumor suppressor gene mutations common to these malignancies are providing bases to elucidate the mechanisms underlying this cancer. The most important basis of endometrial cancer is that K-ras and p53 mutations are also frequently observed.