CA19-9 elevation in ovarian mature cystic teratoma: discrimination from ovarian cancer - CA19-9 level in teratoma.

BACKGROUND: We aimed to identify clinical characteristics of ovarian mature cystic teratoma (MCT) in association with CA19-9 elevation, and to determine if CA19-9 is a useful marker in discrimination of MCT from ovarian cancer (OC). MATERIAL AND METHODS: Medical records of 322 women with pathologically-confirmed MCT or OC (stage 1 or 2) were reviewed retrospectively. The relationships between the characteristics of MCT (mean diameter, bilaterality, and pathologic components) and elevated CA19-9 were evaluated. Tumor markers in MCT were compared to those in OC. RESULTS: MCTs with CA19-9 elevation were correlated with a larger diameter (8.53±3.84 cm vs. 6.95±3.97 cm, p=0.002) and presence of fat component (67.1% vs. 32.9%, p<0.001), compared to those with normal CA 19-9. Although the incidence of CA19-9 elevation was not different between patients with MCT and OC (p=0.700), the mean value of CA19-9 was higher in those with OC (114.66±20.66 U/mL vs. 508.58±261.63 U/mL, p=0.013). In addition, simultaneous elevation of CA125 and CA19-9 was associated with a higher probability of malignant neoplasm (p<0.001; odds ratio: 23.7; 95% confidence interval: 8.863-63.576) than single elevation of CA 19-9. CONCLUSIONS: CA19-9 could be an important tool in the diagnosis of ovarian mature cystic teratoma. CA19-9, in combination with CA125, might be a useful marker in discrimination of MCT from cancer.

Human papillomavirus vaccine: widening the scope for cancer prevention.

Human papillomavirus (HPV) is the necessary cause of cervical cancer. The HPV oncoproteins E6 and E7 have crucial roles in various steps of carcinogenesis, inducing degradation of p53 and destabilization of pRb. Several clinical trials show that recombinant HPV vaccines are safe and effective in preventing persistent infection of HPV and associated anogenital lesions. Although most clinical studies to date have investigated the effectiveness of HPV vaccines in young female subjects, elderly females and males may also be candidates for HPV vaccines. Prophylactic HPV vaccination may be an ideal preventive method for other HPV-associated cancers in addition to cervical carcinoma. Carcinogenesis by HPV, efficacy trials of currently available HPV vaccines, and the possible roles of HPV vaccines in the prevention of HPV-associated cancers are reviewed in this article.

Activation of mTOR signaling pathway associated with adverse prognostic factors of epithelial ovarian cancer.

OBJECTIVE: Activation of the mammalian target of rapamycin (mTOR) pathway enhances cell survival and growth by regulating the efficiency of protein translation. This study was conducted to evaluate the association of activated mTOR signaling molecules with the clinicopathologic characteristics in epithelial ovarian cancer. METHODS: Immunohistochemical staining with antibodies against p-4EBP1, p-mTOR, and p-p70S6K were performed on specimens of 103 patients with ovarian cancer. Tumors were classified as chemoresistant in cases where time to recurrence after the end of chemotherapy was shorter than 6months. RESULTS: Expressions of p-mTOR, p-4EBP1, and p-p70S6K were detected in 47.6%, 85.4%, and 64.1% of all patients, respectively. p-4EBP1 overexpression was associated with advanced stage (p=0.04), histologic grade (p<0.01), residual mass (p<0.01), shorter disease-free survival rate (p=0.01) and chemoresistance (p=0.02). p-p70S6K was associated with residual mass with marginal significance (p=0.06). p-4EBP1 expression was correlated with p-p70S6K expression (r=0.42, p<0.01), whereas p-mTOR was not associated with expression of its downstream effectors or prognostic factors. CONCLUSIONS: Our findings suggest that p-4EBP1 expression was associated with poor prognostic factors of ovarian cancer and that p-4EBP1 overexpression may be a prognostic biomarker of ovarian cancer.

Cyclooxygenase-2 is an independent predictor of poor prognosis in uterine leiomyosarcomas.

INTRODUCTION: Cyclooxygenase-2 (COX-2) is a well-known enzyme that promotes tumor growth and metastasis. Cyclooxygenase-2 is upregulated in a number of human epithelial tumors, but data about the significance of COX-2 in mesenchymal tumors are lacking. The purpose of this study was to determine COX-2 expression in uterine sarcomas and whether a relationship exists between COX-2 expression and clinicopathologic outcomes. METHODS: Immunohistochemical staining for COX-2 was performed on paraffin-embedded tissue blocks of 49 uterine sarcomas (30 leiomyosarcomas, 14 endometrial stromal sarcomas, and 5 carcinosarcomas). Positive staining was defined as moderate or strong staining in 5% or more of tumor cells. RESULTS: Four of 30 leiomyosarcomas, 1 of 14 endometrial stromal sarcomas, and 2 of 5 carcinosarcomas were positive for COX-2 expression. In leiomyosarcomas, COX-2 expression correlated with tumor stage with marginal significance (P = 0.058). Patients with leiomyosarcoma positive for COX-2 expression had a lower overall survival rate than those without COX-2 expression (P = 0.025). In the multivariate Cox proportional hazards regression model, COX-2 expression, tumor stage, and mitotic count were independently associated with overall survival in leiomyosarcomas. CONCLUSIONS: Our data suggest that immunohistochemically determined COX-2 expression is an independent prognostic factor in uterine leiomyosarcomas. Assessment of COX-2 status might be useful for determining the prognosis in patients with uterine leiomyosarcomas.

Quantitative detection of serum survivin and its relationship with prognostic factors in ovarian cancer.

OBJECTIVE: This study was conducted to determine the clinical significance of serum survivin in ovarian cancer. METHODS: A total of 65 patients with ovarian tumors including 21 epithelial ovarian cancer, 22 benign epithelial ovarian tumor, 13 dermoid cyst and 9 endometrioma cases were investigated. All histologic types of cancer were serous carcinoma except for 1 case of undifferentiated carcinoma. ELISA was employed to evaluate the serum survivin levels. For statistical analysis, we used Fisher's exact test, Spearman's correlation coefficient test, the Mann-Whitney U test, the log-rank test and Cox regression analysis. RESULTS: The survivin level was higher in serous ovarian cancer than in benign epithelial tumors with marginal significance. In ovarian cancer, serum survivin was positively correlated with age, advanced stage and poor disease-free survival. Interestingly, high survivin level positivity was associated with positive peritoneal cytology and omental metastasis of ovarian cancer. CONCLUSIONS: Our data collectively suggest that serum survivin reflects the peritoneal metastasis of serous ovarian cancer and may thus be useful as a prognostic biomarker.

Gonadotropin-releasing hormone receptor expression in endometrial cancer.

Several studies have previously reported the expression of the gonadotropin-releasing hormone receptor (GnRHr) in cases of endometrial cancer. However, the relationship between GnRHr expression and a variety of clinicopathologic parameters remains unclear. This study was conducted with 141 endometrial cancer patients, all of whom had undergone operations between 1993 and 2002. Paraffin-embedded tissue blocks were sectioned and immunostained with monoclonal anti-GnRHr antibody. Clinicopathologic variables were also evaluated, with 10% cutoff values for GnRHr positivity. Seventy specimens (49.6%) stained as GnRHr-positive. Mean parity was higher in the patients with GnRHr-positive tumors than those with GnRHr-negative tumors (2.50+/-1.92 versus 1.82+/-1.37, P=0.016). Body mass indices were also higher in the patients with GnRHr-positive tumors (26.6+/-4.6 versus 24.7+/-4.2, P=0.010). However, GnRHr positivity was not determined to be statistically significantly associated with any other clinicopathologic characteristics, including age, menopausal status, histotype, disease stage, tumor differentiation, lymph node metastasis, and myometrial invasion. The results of this study, although they may require further investigation, suggested that obese and multiparous women with endometrial cancer might be greatly influenced by endogenous gonadotropin-releasing hormone and/or exogenous gonadotropin-releasing hormone analogs.

Expression of mTOR protein and its clinical significance in endometrial cancer.

BACKGROUND: Mammalian target of rapamycin (mTOR) plays a crucial role in carcinogenesis by regulating protein synthesis, and mTOR inhibitors have been identified as potential anticancer agents in various cancers. Since the most common genetic change in endometrial cancer is the mutation of phosphatase and tensin homologue (PTEN), a negative regulator of mTOR, we evaluated mTOR expression in endometrial cancer and its relationship with other clinicopathological characteristics and expression patterns of cyclooxygenase-2 (COX-2) and p53. MATERIAL/METHODS: Immunohistochemical analysis of mTOR was performed on paraffin-embedded tissue specimens obtained from 141 patients with endometrial carcinoma. Results were correlated with the clinicopathological characteristics and expression pattern of COX-2 and p53. RESULTS: mTOR overexpression was detected in 7.1% (10/141) of patients. mTOR expression was highly correlated with old age, menopausal status and COX-2 expression (P<0.05). Multivariate analysis revealed that COX-2 was the only independent factor related to expression of mTOR. However, there was no correlation of mTOR expression with prognostic factors such as histologic type, grade, invasion of myometrium, lymph node metastasis, stage, and survival. CONCLUSIONS: Our findings suggest that the expression of mTOR is infrequent and is associated with COX-2 overexpression. Careful selection of patients might be necessary in the use of mTOR inhibitor as a molecular targeted therapy for patients with endometrial cancer.

Influences of cyclooxygenase-1 and -2 expression on the radiosensitivities of human cervical cancer cell lines.

We utilized three cervical cancer cell lines (HeLa, HT-3, and C33A) and clonogenic assays to determine whether cyclooxygenase (COX) expression is related to radiosensitivity. Using COX DNA transfection and COX inhibition by siRNA, we also examined changes in radiosensitivity caused by variations in COX expression. The survival fractions of HeLa and HT-3 cell lines, which both with COX-1 and COX-2 activity, were found to be significantly higher than that of the C33A cell line which had neither COX-1 nor COX-2 activity. Moreover, the acquisition of COX-1 in C33A cell line significantly reduced its radiosensitivity, but COX-2 transfection increased radiosensitivity in this cell line. In addition, the inhibition of COX-1 activity in HT-3 cell line using siRNA resulted in an increased radiosensitivity, but this phenomenon was not observed for COX-2 inhibition. The same experiment in HeLa cells using siRNA also showed no significant change in radiosensitivity. The results obtained during this study suggest that COX expression is associated with the radiosensitivity in uterine cervical cancer cell lines and COX-1 might have more important role than COX-2.

Aromatase expression was not detected by immunohistochemistry in endometrial cancer.

Several studies suggested that aromatase could play an important role in tumor progression and prognosis in endometrial cancer because androstenedione is converted to estrogen by the enzyme. For better understanding of the aromatase expression in endometrial cancer and its relation to diverse clinicopathological parameters, we conducted this study. This study was carried out with 141 endometrial cancer patients, all of whom had undergone operations in our institution from 1993 to 2002. Paraffin-embedded tissue blocks were sectioned and immunostained with monoclonal antiaromatase antibody using human placental tissue as positive control. Clinicopathological variables of all patients were also reviewed. Despite quite a high aromatase expression in positive control, there was no endometrial cancer specimen showing the enzyme expression. Our result, although needs further investigation on the cause of the difference from other studies, suggested that aromatase might not have an important role in endometrial cancer.

Lack of association of the cyclooxygenase-2 and inducible nitric oxide synthase gene polymorphism with risk of cervical cancer in Korean population.

Currently, many studies have shown that nitric oxide (NO) and prostaglandin (PG) are main inflammatory mediators involved in a variety of pathophysiological processes including inflammation and carcinogenesis. In this article, we explored the possible association of polymorphisms, of two representative inflammatory mediators, with the risk for cervical cancer. This study included 176 cases of histologically confirmed invasive cervical cancer, and 172 healthy controls. Allele frequency of 12 single-nucleotide polymorphisms (SNPs) of cyclooxygenase-2 (COX-2) and COX5 of the inducible nitric oxide synthase (iNOS) genes in 43 different normal populations were analyzed. We found that 14 of 17 showed a monomorphic or minimal minor allele frequency; therefore, we did not continue with additional analysis. Three SNPs (2 for COX-2, 1 for iNOS) were chosen for the study. Genotyping of three SNPs (SNP-rs5275 in the untranslated region of exon 10 and rs5277 in the coding region of exon 3 of COX-2, and iNOS Ser(608)Leu allele C/T polymorphism within exon 16 of the iNOS reductase domain) was performed. No significant increase was found in any of the genotypes of the COX-2 or iNOS in the cancer group. We investigated the possible correlation between the genotypes and the clinicopathologic parameters of cervical cancer. No significant association of the genotypes studied was found with respect to clinical stage, lymph node (LN) status, histologic type, or parametrial invasion. Our data did not reveal an association between COX-2 and iNOS polymorphisms with cervical cancer in Korean women.

Increased cyclooxygenase-2 expression associated with inflammatory cellular infiltration in elderly patients with vulvar cancer.

As the relationship between inflammation and carcinogenesis grows stronger, the role of cyclooxygenase-2 (COX-2) and epidermal growth factor (EGFR) has been highlighted in the pathogenesis and progression of human cancer. In view of the fact that vulvar cancer is characterized by precancerous inflammatory changes in elderly patients, the expressions of COX-2 and EGFR are expected to show different patterns of distribution according to age and other prognostic factors. To verify whether there was a relationship between their expression and clinicopathologic parameters in vulvar cancer, we investigated the inflammatory cellular infiltration and the expression of COX-2 and EGFR by immunohistochemical analysis. Eleven of 19 samples (57.8%) were stained positive for COX-2, and 17 (89.4%) for EGFR. The portion of inflammatory cellular infiltration in adjacent normal tissue was also higher in the older age group, and showed a strong correlation with COX-2 positivity (P = 0.002). Furthermore, COX-2 expression was significantly more frequent in patients over 60 years of age compared to those under 50 years (P = 0.009). COX-2 expression was noted to be high in moderate and well-differentiated cases, whereas, poorly differentiated carcinoma was negative for COX-2 expression (P = 0.023). However, EGFR expression was not differently distributed on the basis of stage, age, tumor grading, or presence of lymph node metastasis. Our article suggests that vulvar cancer in elderly patients may be associated with inflammation, and thus with increased COX-2 expression. In light of these findings, a clinical trial designed to assess the addition of COX-2 targeted therapy to conventional treatment in vulvar cancer would be helpful for consideration of additional treatment options and possibly avoiding the serious surgical morbidity in elderly patients.

NF-kappaB as a potential molecular target for cancer therapy.

Nuclear factor kappaB (NF-kappaB), a transcription factor, plays an important role in carcinogenesis as well as in the regulation of immune and inflammatory responses. NF-kappaB induces the expression of diverse target genes that promote cell proliferation, regulate apoptosis, facilitate angiogenesis and stimulate invasion and metastasis. Furthermore, many cancer cells show aberrant or constitutive NF-kappaB activation which mediates resistance to chemo- and radio-therapy. Therefore, the inhibition of NF-kappaB activation and its signaling pathway offers a potential cancer therapy strategy. In addition, recent studies have shown that NF-kappaB can also play a tumor suppressor role in certain settings. In this review, we focus on the role of NF-kappaB in carcinogenesis and the therapeutic potential of targeting NF-kappaB in cancer therapy.

Steroid receptor expressions in endometrial cancer: clinical significance and epidemiological implication.

The evaluation of expression levels of the estrogen receptor (ER) and progesterone receptor (PR) in endometrial cancer is a very common procedure in modern practice. However, the significance of such tests remains controversial, and the evaluation of the status of steroid receptors seems to be a more thoroughly justified practice. The present study was carried out with 145 endometrial cancer patients, all of whom had undergone operations at the Seoul National University Hospital, from 1993 to 2002. Paraffin-embedded tissue blocks were sectioned and immunostained with monoclonal anti-ER and anti-PR antibodies. Clinicopathological variables were also analyzed, with 10% cutoff values for ER and PR positivity. A multivariate Cox regression analysis was performed in order to estimate the influences of several clinicopathological and immunohistochemical covariates on patient survival. Forty seven specimens (32.4%) stained as ER positive, and 110 (75.9%) stained as PR-positive. Patients with PR-positive tumor tended to be both younger and more obese than patients with PR-negative tumors (P=0.020, 0.016). Well-differentiated tumors were found to be positive for ER or PR more frequently (P=0.015, <0.001). ER or PR-positive tumors exhibited significantly less myometrial invasion (P=0.042, 0.002). However, multivariate Cox regression analyses revealed that the expressions of ER and PR were not significantly associated with patient survival, and only advanced FIGO stage constituted an independent prognostic factor. Our results suggested that the evaluation of steroid receptors might prove helpful prior to surgery. Low ER and high PR values suggest that racial differences and/or sequential loss of receptors during carcinogenesis might be involved in the expression of steroid receptors in cases of endometrial cancer.

Cyclin D1 G870A polymorphism and squamous cell carcinoma of the uterine cervix in Korean women.

Though many investigators have reported relationships between the CCND1 polymorphism and susceptibility to various carcinomas, to our knowledge, no report has been issued concerning its relationship with uterine cervical cancer. Thus, we undertook this study to investigate the association between CCND1 polymorphisms and susceptibility to cervical cancer in Korean women. This study was carried on 222 patients with squamous cell carcinoma of uterine cervix and on 314 normal controls. CCND1 genotyping was determined by polymerase chain reaction and restriction fragment length polymorphism. The allelic frequencies of the cases (A, 0.53; G, 0.47) were not significantly different from those of the controls (A, 0.49; G, 0.51) (P=0.238). Regression analysis after adjusting for age showed that the CCND1 G870A genotypes are not related to the risk of squamous cell carcinoma of the uterine cervix. Our findings suggest that the CCND1 polymorphism is not associated with an increased risk of squamous cell carcinoma of uterine cervix in Korean women.

Sequence variation and the transcriptional activity of the upstream regulatory region in human papillomavirus 16 E7 variants in cervical cancer of Korean women.

In this study, we investigated the sequence variation and different transcriptional activities of the upstream regulatory region (URR) in HPV 16 E7 variants in cervical cancer tissue from Korean women. Using PCR-directed sequencing, the presence of sequence variations in URRs were analyzed and the sites of sequence variation were matched with the known transcriptional factor binding site (TFBS) in 26 HPV 16 E7 variants, 21 cases with A647G (KE7-1, high oncogenic potential) and 5 cases with T732C (KE7-2, low oncogenic potential). In addition, we determined the transcriptional activity of URR in a HPV 16 prototype, and in 4 cases of HPV 16 E7 variants, by using the functional chloramphenicol acetyl transferase (CAT) assay. The 26 HPV 16 E7 variants showed more than 11 sites of sequence variation in the URR. Ten sites of sequence variation were located in the known TFBS and the distribution of sequence variations in the URR showed clear differences between KE7-1 and KE7-2. The sequence variations T7781C and C7786T were matched with YY1 binding sites, G7193T and C7689A were matched with TEF1 binding sites, and C7394T and C7395T were matched with GRE binding sites. The other sequence variations, which were matched with the TFBS, were A7485C, G7489A, T7743G and G7842A. The URR activity of KE7-1 was significantly lower than that of the HPV 16 prototype, whilst KE7-2 was similar. Taken together with the results of the transcriptional activities of KE7-1 and KE7-2, our results suggest that the functional activity and sequence variations of HPV 16 URR may not be related to the oncogenic potential of HPV 16 E7 variants.

Cyclooxygenase-2 and p53 expressions in endometrial cancer.

Cyclooxygenase-2 (COX-2) has been known to be related with various types of carcinoma, but we have insufficient knowledge about the association between COX-2 and endometrial cancer. Many have reported a close relationship between p53 expression and a poor prognosis in endometrial cancer, but it is unclear whether p53 is an independent prognostic factor. To clarify these uncertainties, we examined the expressions of COX-2 and p53 in endometrial cancer tissues. The study was carried on 152 endometrial cancer patients who had operation at Seoul National University Hospital. Paraffin-embedded tissue blocks were sectioned and immunostained using monoclonal anti-COX-2 and anti-p53 antibodies. Twenty-seven (17.8%) specimens stained as COX-2 positive. COX-2 positivity was more frequently observed in postmenopausal patients than in premenopausal patients (8.8% versus 25.0%; P = 0.009). However, COX-2 positivity did not show a statistically significant association with any other clinicopathologic characteristic (parity, body mass index, histotype, International Federation of Gynecology and Obstetrics stage, grade, lymph node metastasis, deep myometrial invasion, or p53 overexpression). Thirty-one (20.4%) specimens showed p53 overexpression and this was significantly correlated with an advanced stage (P = 0.001), poor differentiation (P < 0.001), lymph node metastasis (P = 0.012), and deep myometrial invasion (P < 0.001). Multivariate Cox regression analysis showed that advanced stage was an independent prognostic factor of survival, but p53 overexpression was not. COX-2 may be associated with endometrial cancer carcinogenesis during the postmenopausal period but not with tumor aggressiveness and p53 overexpression. The p53 overexpression was found to be strongly associated with endometrial cancer aggressiveness.

Multiple HPV infection in cervical cancer screened by HPVDNAChip.

This study determined the distribution of high-risk HPV type infection in cervical cancer using newly developed oligonucleotide chips (HPVDNAChips). The study subjects included 80 cases of cervical neoplasia and 746 controls with a normal Pap smear. For HPV genotyping, the commercially available HPVDNAChips was used. The risk of cervical cancer was increased in women with a family history of cervical cancer (adjusted OR=2.3, 95% CI: 0.92-6.17) and in smokers (adjusted OR=3.2, 95% CI: 1.45-7.06). There was also a trend of increased risk with the number of full term pregnancies (P(for trend)<0.001). There were only 7.2% (54 of 746) infected high-risk HPV types in the control, whereas 54.5% (six of 11) and 76.5% (52 of 68) were infected in the CIN and cervical cancer, respectively. Multiple HPV infection was observed in 0.5% (three of 592) of the control group but in 9.1% (seven of 77) of cases. Multivariate analysis revealed that subjects infected with multiple HPV types had a 31.8-fold (95% CI: 7.50-134.75) higher risk of cervical cancer, while the single HPV type had a 19.9-fold increased risk (95% CI: 10.90-36.18) (P(for trend)<0.001). These results show that the detection and typing of HPV infection by HPVDNAChip can be a useful in clinical applications because it provides information on multiple infections and the types of HPV in addition to HPV infection status.

Prognostic value of biomarkers related to drug resistance in patients with advanced epithelial ovarian cancer.

BACKGROUND/AIM: We aimed to investigate the prognostic value of biomarkers [Ki-67, adenosine triphosphate-binding cassette sub-family B member 1 (ABCB1), adenosine triphosphate-binding cassette sub-family C member 1 (ABCC1), adenosine triphosphate-binding cassette sub-family C member 2 (ABCC2), p53, cyclin E and v-akt murine thymoma viral oncogene homolog 2 (AKT2)] in patients with advanced epithelial ovarian cancer (EOC). MATERIALS AND METHODS: The levels of expression of biomarkers in tumor tissues of 47 patients with stage 3 or 4 EOC were estimated via immunohistochemical staining using tissue microarrays. The associations of biomarker expression with progression-free survival (PFS) and overall survival (OS) were evaluated using a log-rank test and Cox regression analysis. RESULTS: Based on multivariate analysis, high expression of Ki-67 (p=0.003) and low expression of ABCC2 (p=0.048) were associated with a prolonged PFS. However, other biomarkers were not associated with PFS. Residual tumor <1 cm (p=0.023) and PFS >6 months (p=0.005) were associated with prolonged OS. However, none of the biomarkers were associated with OS. CONCLUSION: High expression of Ki-67 and low expression of ABCC2 appear to be useful as markers for prolonged PFS in patients with advanced EOC.

A case of clear cell carcinoma arising from the endometriosis of the paraovarian cyst.

Malignant transformation of endometriosis is an infrequent complication. Clear cell carcinoma from endometriosis is very rare in the paraovarian cyst. To date no cases have been reported. We report a case of clear cell carcinoma arising from endometriosis of the paraovarian cyst with a brief review of literature.

Genistein inhibits cell growth by modulating various mitogen-activated protein kinases and AKT in cervical cancer cells.

Genistein, a soy-derived isoflavone, inhibits growth of tumor cells from various malignancies. Here we investigated the effect of genistein on the growth of cervical cancer cells (HeLa and CaSki) and its possible mechanism. Genistein significantly suppressed cell growth of HeLa and CaSki cells at concentrations of 20 and 60 micromol/L, respectively, for 24 h. Western blotting analysis showed that genistein reduced phosphorylation of AKT and extracellular signal-regulated kinase (ERK)-1/2 and induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK). Moreover, inhibition of ERK1/2 activity enhanced cell growth inhibition by genistein, whereas inhibition of p38 MAPK activity rescued from genistein-mediated growth inhibition. Interestingly, inhibition of AKT activity recovered genistein-induced growth inhibition in CaSki cells but did not in HeLa cells. However, inhibition of JNK activity seemed to have little effect on cell growth inhibition by genistein. Taken together, these results suggest that genistein could inhibit cell growth by inhibiting ERK1/2 activity and activating p38 MAPK.