Impact of Expression Levels of Platinum-uptake Transporters Copper Transporter 1 and Organic Cation Transporter 2 on Resistance to Anthracycline/Taxane-based Chemotherapy in Triple-negative Breast Cancer

Adding platinum drugs to anthracycline/taxane (ANC-Tax)-based neoadjuvant chemotherapy (NAC) improves pathological complete response (pCR) rates in triple-negative breast cancer (TNBC). Copper transporter 1 (CTR1) and organic cation transporter 2 (OCT2) critically affect the uptake and cytotoxicity of platinum drugs. We immunohistochemically determined CTR1 and OCT2 levels in pre-chemotherapy biopsies from 105 patients with HER2-negative breast cancer treated with ANC-Tax-based NAC. In the TNBC group, Ki-67 high [pathological good response (pGR), P = 0.04] was associated with response, whereas CTR1 high (non-pGR, P = 0.03), OCT2 high (non-pGR, P = 0.01; non-pCR, P = 0.03), and combined CTR1 high and/or OCT2 high (non-pGR, P = 0.005; non-pCR, P = 0.003) were associated with non-response. In multivariate analysis, Ki-67 high was an independent factor for pGR and CTR1 for non-pGR. Combined CTR1/OCT2 was a strong independent factor for non-pGR. However, no variables were associated with response in luminal BC. These results indicate that platinum uptake transporters are predominantly expressed in ANC-Tax-resistant TNBCs, which implies that advantage associated with adding platinum drugs may depend on high drug uptake

Association of the hypoxia-inducible factor-1α (HIF-1α) gene polymorphisms with prognosis in ovarian clear cell carcinoma

Abstract Background Ovarian clear cell carcinoma (OCCC) is the second most common ovarian cancer after serous carcinoma in Japan. OCCC has a more unfavorable clinical outcome due to a poor response to platinum-based chemotherapy, compared with serous carcinoma. Hypoxia inducible factor-1α (HIF-1α) is a key regulator of cellular response to hypoxia and plays an important role in tumor growth, and HIF-1α gene single-nucleotide polymorphisms (SNPs) adversely affect the outcome in some cancers. Herein, we investigated the association of the HIF-1α gene SPNs with clinical outcome in OCCCs. Eighty-nine patients with OCCC were recruited in whom pathological diagnosis was confirmed with surgically resected specimen. Results The SNPs of C1772T and G1790A in the HIF-1α gene occurred in 23.6 and 3.3% of the patients, respectively. In the univariate analysis, overall survival was associated with stage and surgical residual tumor but not with the SNPs C1772T, G1790A, C1772T and/or G1790A. In the multivariate survival analysis, a significant association was observed between outcome and FIGO stage and/or surgical residual tumor; however, no association was obtained between HIF-1α gene SNPs and these factors. Conclusion In conclusion, unlike the other cancers in which HIF-1α gene SNPs were demonstrated to be associated with the outcome, OCCC prognosis may not be affected by HIF-1α gene SNPs. Further studies need to be performed to clarify the association of HIF-1α expression with the unfavorable prognosis in OCCCs, in terms of transcriptional/translational activity, nuclear translocation of the protein, and protein degradation