High expression of thymidine phosphorylase in basal-like breast cancers: Stromal expression in EGFR- and/or CK5/6-positive breast cancers

Abstract

Expression of the estrogen receptor (ER), the progesterone receptor (PgR) or the human epidermal growth factor receptor-2 (HER2) in tumors is a good prognostic marker for breast cancer patients. However, approximately 15-20% of breast cancer patients have triple-negative breast cancer (TNBC; negative for ER, PgR and HER2), and efficient therapeutic modalities for these patients are under investigation. We focused on thymidine phosphorylase (TP), an enzyme metabolizing 5'-DFUR, an intermediate of capecitabine, to 5-fluorouracil in order to investigate the application of well-known therapeutics for TNBC. Results of a gene expression analysis showed that TP expression in TNBC and basal-like breast cancer (BLBC) was higher than that of other subtypes. Immunohistochemically, the high expression of TP in TNBC and BLBC reflected expression in stromal but not tumor cells. Notably, a high TP expression was observed in the stromal cells of EGFR- and/or CK5/6-positive breast tumors. Our present results showing a high expression of TP in BLBC indicate that capecitabine-based chemotherapy would be of benefit for patients with TNBC.

Figure 1

Box plot of TP mRNA expression in breast tumors. Plots were scaled by dividing each median value. TP mRNA expression in (A) breast tumor and adjacent normal tissues, (B) ER-positive and ER-negative breast tumors, and (C) HER2-positive and HER2-negative breast tumors. (D) Multivariate analysis of TP expression in ER-positive/HER2-positive, ER-positive/HER2-negative, ER-negative/HER2-positive and ER-negative/HER2-negative breast tumors. TP mRNA expression in (E) triple-negative breast cancer (ER/PgR/HER2-negative, TNBC) and non-TNBC, (F) basal-like breast cancer (BLBC) and non-BLBC. Statistical analysis was performed by the Mann-Whitney U test (A-C, E and F) or by one-way analysis of variance followed by Dunnett’s t-test (D). P<0.05 was considered statistically significant (^*p<0.05, ^**p<0.01).

Figure 2

(A) Typical immunohistochemical TP expression patterns showing no expression in cancer cells or stroma (top left), positive expression in stroma (top right), positive expression in cancer cells (bottom left) and positive expression in both cancer cells and stroma (bottom right). (B) Correlation between TP mRNA and protein expression.

Figure 2

(A) Typical immunohistochemical TP expression patterns showing no expression in cancer cells or stroma (top left), positive expression in stroma (top right), positive expression in cancer cells (bottom left) and positive expression in both cancer cells and stroma (bottom right). (B) Correlation between TP mRNA and protein expression.

Figure 3

Box plot for total (A) and stromal (B) TP immunohistochemical scores in ER/PgR-positive/HER2-negative, ER/(PgR)^*/HER2-positive, ER/PgR-negative/HER2-positive and ER/PgR/HER2-negative breast tumors (^*7/10 tumors were positive for PgR). Plots were scaled by dividing each median value.

Figure 4

Box plot of immunohistochemical scores for TP expression of stromal cells in EGFR-positive (A), CK5/6-positive (B), EGFR-positive/CK5/6-positive breast tumors (C), triple-negative breast cancer (D) and basal-like breast cancer (E). Plots were scaled by dividing each median value.