High expression of ATP-binding cassette transporter ABCC11 in breast tumors is associated with aggressive subtypes and low disease-free survival

Abstract

ATP-binding cassette (ABC) transporters are membrane proteins that efflux various compounds from cells, including chemotherapeutic agents, and are known to affect multidrug resistance. Recent reports disagree on whether ABCC11 is a risk factor for breast tumorigenesis, but its expression in breast cancer is poorly investigated. We hypothesized that both frequency and expression levels of ABC transporters in breast tumors would vary by cancer subtype, and be associated with prognosis. Here, we constructed a tissue microarray breast tumor samples from 281 patients, and analyzed expressions of ABCB1, ABCC1, ABCC11, and ABCG2 immunohistochemically. Breast cancer subtypes were determined by immunohistochemistry of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2). Protein expression was correlated to clinicopathological characteristics, clinical follow-up, and pathological complete response to neoadjuvant chemotherapy. The tissue microarray comprised 191 luminal A (68.0%), 17 luminal B (6.0%), 27 HER2 (9.0%), and 46 triple-negative (16.4%) samples. ABCC1 and ABCC11 expressions were associated with significantly shorter disease-free survival (P = 0.027 and P = 0.003, respectively). ABCC1, ABCC11, and ABCG2, but not ABCB1, were expressed significantly more, and more frequently, in aggressive subtypes. Patients with HER2+ and triple-negative tumor subtypes that expressed high levels of ABCC11 had significantly worse disease-free survival (P = 0.017 and P < 0.001, respectively). We have shown, for the first time, that ABCC1, ABCC11 and ABCG2 are highly expressed in aggressive breast cancer subtypes, and that tumor ABCC11 expression is associated with poor prognosis.

Export of sphingosine-1-phosphate and cancer progression

“…by guest, on May 9, 2018 www.jlr.org Downloaded from survival (55). Thus, we speculate that S1P export from cancer cells by ABC transporters might enhance cancer progression and contribute to the phenotype of mul tidrug resistance.…”

Multidrug Resistance Proteins (MRPs) and Cancer Therapy

“…However, the effect of MRP8 genotypes on breast cancer is likely to be more complex since there are studies showing that the association could not be observed in Caucasian (82). Although there is a report showing a decrease in MRP8 level in breast cancer (83), high level of MRP8 was reported in breast cancer and gastric cancer cell lines by other groups (84,85). Other substrates of MRP8 include MTX (79), 5-FU, and pemetrexed (86,87).…”

“…Recently, Akimitsu et al showed that in the aggressive breast carcinoma subtypes, there is an overexpression of MRP1 and MRP8 (85). In another study, it has been shown that MRP1, MRP2, and MRP3 are expressed in lung cancer patients, with differences in the lung cancer subtypes (90).…”

Clinical Relevance of Multidrug-Resistance-Proteins (MRPs) for Anticancer Drug Resistance and Prognosis

“…Although MRP8 has been associated with a poor prognosis in all subtypes except luminal A [ 171 ], mRNA and protein expression were decreased in cancer compared to normal breast tissue [ 144 ]. In addition, SNPs within MRP8 have also been linked with cancer risk in 270 Japanese patients [ 120 ] but this association was not observed in European cohorts [ 8 , 86 ].…”

“…In breast cancer and ovarian cancer, where histological subtypes are more clearly defi ned, MRP expression appears to correlate with a more aggressive phenotype. MRP1 was more frequently expressed in both high-risk resistant triple-negative (Human Epidermal Growth Factor Receptor 2 (HER2), oestrogen and progesterone receptor negative) breast cancer [ 171 ] and stage 1C endometrial carcinoma [ 82 ] than in other subtypes. Furthermore, expression of MRP1 predicted a worse OS in these groups [ 82 , 171 ], consistent with the classical markers of adverse prognosis in these subtypes [ 30 , 36 ].…”