Breast cancer is one of the most frequent and deadly cancers in women, with an estimated 1,300,000 new cases and 465,000 deaths annually . Multidrug resistance is one of the main impediments to the successful treatment of breast cancer. The mechanisms underlying MDR are complex and overexpression of P-gp is considered to be an important factor.
Recent research has indicated that the expression of P-gp is related to the activity of GCS, an enzyme that glycosylates ceramide and inhibits its proapoptotic activity in cells. Zhang et al. revealed that the expression of the GCS gene in the drug-resistant human breast cancer cell line MCF-7/ADM is higher than that in drug sensitive cells, and that the sensitivity of MCF-7/ADM cells to adriamycin is enhanced by GCS inhibition . Furthermore, GCS expression has been found to confer MDR in many other cancers [19, 20]. MDR1 and GCS have been shown to be overexpressed coincidently in several drug-resistant cell lines, a phenomenon that indicates a relationship between these two proteins. In 2010, Liu et al. demonstrated for the first time that GCS upregulates MDR1 expression resulting in the modulation of drug resistance in the ovarian drug-resistant cell line NCI/ADR-RES through the cSrc and beta-catenin signaling pathway .
In 2009, microarray analysis of 1,681 breast tumors conducted by Ruckhäberle et al. revealed that GCS mRNA expression was associated with positive ER status, lower histological grading, low Ki67 levels and ErbB2 negativity (P < 0.001 for all) . In 2011, Liu et al. detected GCS expression levels in normal tissues and certain cancer tissues. Their results showed that GCS overexpression is highly associated with ER-positive and HER-2-positive breast cancers that have metastasized ; however, this was a small study. Our results demonstrated that GCS protein expression was higher in ER-positive samples (P < 0.05) (Table 3), which was in accordance with both of these previous studies.
Human epidermal growth factor receptor 2 (HER2) protein, encoded by the oncogene HER2, is amplified in 20–30% of breast cancer cases and is the target of HER2-directed anti-cancer therapies . Our research shows that there was a significant correlation between GCS expression and low HER-2 status in the invasive ductal cancer samples (Table 3), which was in accordance with the study of Ruckhäberle et al., although our observation that GCS protein levels did not correlate with Ki67.
Our study demonstrated a higher positive rate of GCS expression in breast cancer samples from younger patients (aged <35 years) expressed lower levels of GCS protein than older patients (aged ≥35 years) (60% vs. 74.8%, P = 0.035). Otherwise, we found that the expression of GCS was higher in the cancer T1-2 than that in the cancer T3-4.
Breast cancer is accounting for 23% (1.38 million) of the total new cancer cases and 14% (458,400) of the total cancer deaths in 2008 worldwide. Metastasis and recurrence severely affect the quality and length of lives of breast cancer patients . Although the study of Liu demonstrated that GCS overexpression is highly associated with ER-positive and HER-2-positive breast cancers that have metastasized , our study demonstrated that GCS expression has no correlation with lymph metastasis.
Our data also showed that, in contrast to previous reports, GCS protein expression was much higher in DCIS than that in the invasive ductal cancer.