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

Solute carrier transporters, reduced folate carrier 1 and equilibrative nucleoside transporter 1, as immunohistochemical markers for high-grade malignancy in bladder cancer

Clinicopathological parameters derived from initial transurethral resection of bladder tumor (TUR-Bt) have limitations in predicting tumor progression in bladder cancer. Reduced folate carrier 1 (RFC1) and equilibrative nucleoside transporter 1 (ENT1) are solute carrier (SLC) transporters supporting cellular uptake of endogenous bioactive substances and anti-cancer drugs. The aim of this study was to elucidate the role of SLC transporters in bladder cancer and investigate the potential of RFC1 and ENT1 expression as immunohistochemical markers for high-grade malignancy. We compared T-stage with the immunohistochemical expression of RFC1 and ENT1 and other clinicopathological parameters; moreover, we also used multiple logistic regression model to assess relative contributions for T-stage in bladder cancer (n=130). Concurrently, 57 TUR-Bt-derived imprint cytological samples were stained to evaluate the implication of cytological analysis. Elevated expression levels of RFC1 and ENT1 were significantly correlated with higher T-stage (p < .0001) and efficiently predicted tumor progression, compared with other clinicopathological parameters (RFC1, p = .0325; ENT1, p = .0171). Independent variables of optimal model for predicting T-stage were gender, age, histological grade, expression levels of RFC1 and ENT1. Cytological analysis was consistent with immunostained-tissue data. We reveal RFC1 and ENT1 as potential immunohistocytochemical markers for high-grade malignancy in bladder cancer

Enzyme-labeled Antigen Method: Histochemical Detection of Antigen-specific Antibody-producing Cells in Tissue Sections of Rats Immunized With Horseradish Peroxidase, Ovalbumin, or Keyhole Limpet Hemocyanin

The enzyme-labeled antigen method is a histochemical technique that visualizes antigen-specific antibody-producing cells in tissue sections, originally documented in 1968. In this study, we attempted to reemerge this hidden but potentially useful method in rat models immunized with horseradish peroxidase (HRP), ovalbumin (OA), or keyhole limpet hemocyanin (KLH). After repeated immunization in footpads, popliteal, groin, and axillary lymph nodes and spleen were sampled. Paraformaldehyde-prefixed frozen sections were incubated with HRP, biotinylated OA, or biotinylated KLH. Proteinase K pretreatment and the secondary use of HPR-labeled streptavidin were applied in the latter two situations. Plasma cells producing antigen-specific antibodies were visualized. Proportions of antigen-specific antibody-producing cells in total plasma cells shown with the immunoperoxidase method for rat immunoglobulins were evaluated. The percentage of antigen-specific plasma cells reached ∼50% of total plasma cells in the regional lymph nodes. The specificity was confirmed by (a) negativity in non-immune rat tissue, (b) negativity with indifferent antigen probes, and (c) abolishment of the reactivity with the corresponding rat serum. In buffered formalin-fixed, paraffin-embedded tissues, fewer plasma cells were labeled for HRP and KLH antibody reactivity after strong proteolysis and prolonged incubation. Expectedly, this method allows us to observe antigen-specific antibody-producing cells under varied pathological conditions. (J Histochem Cytochem 57:101–111, 2009