ABSTRACT:The aim of the present study was to assess the contribution of polymorphisms in the breast cancer resistance protein/ATP-binding cassette transporter G2 (BCRP/ABCG2) gene to the placental expression from a new perspective, allelic imbalance. Polymorphisms were screened by polymerase chain reaction (PCR)-singlestrand conformation polymorphism analysis followed by sequencing with DNA extracted from 100 placentas. To evaluate whether the C421A polymorphism acts as a cis-element in BCRP transcription, allelic imbalance was determined using informative lymphoblasts and 56 samples of placental cDNA. In most of the placental samples we tested, the difference in expression levels between the two alleles was small, and only two samples indicated a monoallelic expression (i.e., preferential expression of one allele). These results suggest that 1) the predominant allelic expression pattern of BCRP in placental samples is biallelic, and 2) the mutation C421A is not a genetic variant acting in cis, but is considered to influence the translation efficiency.Breast cancer resistance protein (BCRP), also called mitoxantroneresistant protein, is the second member of the G family of ATPbinding cassette transporters (ABCG2) (Allikmets et al., 1998;Doyle et al., 1998;Miyake et al., 1999;Doyle and Ross, 2003). The BCRP gene is located at 4q22 and encodes a 72-kDa membrane protein composed of 655 amino acids (Allikmets et al., 1998;Doyle et al., 1998;Allen et al., 1999;Bailey-Dell et al., 2001). In contrast to many other ABC transporters, BCRP has only one ATP-binding region and one transmembrane domain. Therefore, BCRP is referred to as a half-transporter, and its homodimerization may be necessary to transport substrates .In normal human tissues, BCRP is highly expressed in the placenta, colon, small intestine, and liver (Maliepaard et al., 2001). On the basis of its tissue distribution and findings in knockout mice, BCRP is speculated to have a major influence on the pharmacokinetic and pharmacodynamic profiles of certain xenobiotics and endogenous substrates. For example, inhibition of mouse Bcrp 1 by GF120918, a dual inhibitor for BCRP and P-glycoprotein, has been demonstrated to increase the bioavailability of topotecan when GF120918 was administered orally to mdr1a/1b(Ϫ/Ϫ) mice (Jonker et al., 2000). In a clinical study, coadministration of GF120918 was also associated with a marked increase in the bioavailability of and systemic exposure to topotecan (Kruijtzer et al., 2002).Recent clinical studies indicate that the large interindividual variability in drug response occurs as a result of molecular alterations to various proteins such as drug-metabolizing enzymes, drug targets and receptors, and drug transporters. Most studies on molecular alterations have focused on the impact of single-nucleotide polymorphisms (SNPs) on the expression and function of these proteins (Evans and Relling, 1999;Evans and Johnson, 2001). Several groups have reported naturally occurring SNPs in the BCRP gene. G34A and C421A occur at relative...

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A retrospective analysis was performed to evaluate the clinical characteristics and prognostic factors in the patients with clear cell carcinoma (CCC) of the ovary. After central pathological review and scanning of the medical records of nine Japanese institutions between 1992 and 2003, a total of 254 patients with CCC of the ovary were enrolled in the present study. Mean age was 52.4 years (range 23 -73 years). Tumours were 13% (33/254) stage Ia, 36% (92/254) stage Ic, 13% (33/254) stage II, 30% (80/254) stage III, and 6% (16/254) stage IV. Five-year progression-free survival and overall survival was 84 and 88% in stage I, 57 and 70% in stage II, 25 and 33% in stage III and 0 and 0% in stage IV, respectively. Retroperitoneal lymph node metastasis was observed in 9% in pT1a tumours, 7% in pT1c tumours, 13% in pT2 tumours, and 58% in pT3 tumours, respectively. There was no survival benefit according to chemotherapeutic differences in the patients who received complete surgical staging procedures and conventional chemotherapy. Peritoneal cytological status was an independent prognostic factor in stage Ic patients (P ¼ 0.03) and only residual tumour diameter was an independent prognostic factor in stage III, IV patients (P ¼ 0.02). Our results suggest that cytoreductive surgery resulting in no residual tumour only could improve the prognosis of advanced CCC patients.

Clear cell carcinoma (CCC) accounts for 4% to 12% of epithelial ovarian cancer in Western countries and, for some unknown reasons, it comprises more than 20% of such cancers in Japan. CCC shows unique clinical features such as a high incidence of stage I disease, a large pelvic mass, an increased incidence of vascular thromboembolic complications, and hypercalcemia. It is frequently associated with endometriosis. Compared to serous adenocarcinoma (SAC), CCC is relatively resistant to conventional platinum, or taxane-based chemotherapy which is associated with its poor prognosis. However, the mechanisms underlying CCC's resistance to chemotherapy have not been understood. Although several mechanisms involved in drug resistance exist in CCC, including decreased drug accumulation, increased drug detoxification, and an increased DNA repair activity; however, no particular chemoresistance system has been identified. On the other hand, an in vitro study revealed that low cell proliferation may cause the insensitivity of CCC to cisplatin. The Ki-67 labeling index in CCC tumors was significantly lower than SAC. The Ki-67 labeling index for responders was significantly higher than that for non-responders in both tumor types. A multivariable analysis revealed that Ki-67 labeling index and residual tumor size were independent prognostic factors in CCC. Therefore, lower proliferation of the tumor cells may contribute to their resistance to chemotherapy. However, further investigation into the molecular biology and genetics of CCC is warranted. This review discusses the current state of knowledge of the chemoresistance mechanism in CCC and novel treatment strategies for CCC. (Cancer Sci 2008; 99: 653-658)

Purpose: To clarify the diagnostic accuracy of diffusionweighted imaging (DWI) in differentiating benign from malignant ovarian lesions. Materials and Methods:We retrospectively analyzed magnetic resonance images of 123 ovarian lesions in 119 patients. We defined lesions with abnormal signal intensity as malignancy and assessed the location of abnormal intensity within the lesions on DWI. We also assessed the mean and lowest apparent diffusion coefficient (ADC) values of the solid portion for each ovarian lesion. Results:The majority of malignant ovarian tumors and mature cystic teratomas, and almost half of the endometriomas, showed abnormal signal intensity on DWI, whereas most fibromas and other benign lesions did not. The main locations of abnormal signal intensity were solid portions in malignant ovarian tumors, cystic components suggestive of keratinoid substances and Rokitansky protuberance in mature cystic teratomas, and intracystic clots in endometriomas. On DW imaging, receiver-operating characteristic analysis yielded mean Az values of 0.703. There was no significant difference in mean and lowest ADC values between malignant and benign lesions.Conclusion: DWI of ovarian lesions and ADC values of the solid component are not useful for differentiating benign from malignant ovarian lesions. This knowledge is essential in avoiding misinterpretation in the diagnosis of ovarian lesions.