C-KIT expression increased from low grade (0%) to high-grade (50%) IDC, but this was statistically not significant (P=0.14). All IDC cases that expressed C-KIT were negative for lymph node metastasis. There was a significant association between negative expression of the C-KIT protein and lymph node metastasis (P=0.04). Also, C-KIT expression did not show significant difference with respect to the patient’s age and the tumor size (Table 2).
In invasive breast cancer, HER-2/neu expression was detected in only four (13.3%) of 30 cases. However, we found that 50% (two of four cases) of the HER-2/neu-positive cases and 11.5% (three of 26 cases) of the HER-2/neu-negative cases coexpressed C-KIT. This was statistically nonsignificant (P=0.11). ER and PR were detected in 16 (53.3%) and 17 (56.6%) of the 30 cases of IDC, respectively. Only one of the ER (6.2%) and none of the PR-positive IDC coexpressed C-KIT, which was significantly decreased in PR-positive IDC (P=0.009) (Table 3).
In breast cancer, the expression of C-KIT represents a highly controversial subject (Amin et al., 2012). In the present study, we investigated the expression of C-KIT within the spectrum of normal breast epithelium, benign breast lesions, and breast cancer to evaluate its potential role in malignant transformation and other prognostic parameters.
In our study, there was a highly significant difference in C-KIT expression between tumor tissues (16.6%) and normal (100%) and benign breast lesions (75%) (P<0.001). Similar results were reported by others (Natali et al., 1992; Chui et al., 1996; Palmu et al., 2002; Tsuura et al., 2002; Ko et al., 2003; Ulivi et al., 2004; Yared et al., 2004; Tsutsui et al., 2006), who found that the rate of a positive C-KIT expression in the normal breast tissue was 100% and the rate of positive C-KIT expression or its immunohistochemical score (IRS) in benign tumors was always lower than that of normal breast tissue and always higher than that of breast cancer, which varies from 1 to 82%. In contrast, Eroǧlu and Sari (2007) found that in breast cancer tissues, the mean IRS of C-KIT expression was significantly increased compared with those of fibroadenomas. Also, Roussidis et al. (2007) found a higher rate of C-KIT expression in breast cancer than that of normal breast tissue and benign breast tumors. Moreover, in their work on breast cancer, Amin et al. (2012) found C-KIT expression in 28.6% of the cases, whereas Kashiwagi et al. (2013) found C-KIT expression in 16.6% of the cases, which is very similar to our results.
In our study, C-KIT immunoreactivity was detected in the stromal cells of high-grade breast carcinoma. Similar results were also reported by Kondi-Pafiti et al. (2010) and Amin et al. (2012). However, Kondi-Pafiti et al. (2010) reported that C-KIT was highly expressed in the stromal cells of high-grade breast carcinoma despite negative C-KIT expression in tumor cells. Tumor stromal cells may contribute to the establishment of a more permissive microenvironment for tumor growth and progression (Joyce and Pollard, 2009). Moreover, Dabiri et al. (2004) also demonstrated that the presence of C-KIT-positive mast cells in the peritumoral stroma correlated with a good prognosis in breast cancers with long-term follow-up.
In our study, we found a significant association between C-KIT expression and negative lymph node metastasis (P=0.04), but did not find a significant difference with respect to the tumor grade, patients’ age, and the tumor size. The association between negative C-KIT expression and lymph node metastasis has been reported previously by Tsutsui et al. (2006) and Amin et al. (2012). However, Chui et al. (1996), Simon et al. (2004), and Ulivi et al. (2004) did not find any significant correlation between C-KIT expression and lymph node metastasis. In contrast, Shams and Shams (2011) and Kashiwagi et al. (2013), in their work on triple-negative breast cancer, found a significant correlation between C-KIT expression and lymph node metastasis. In addition, a significant correlation between positive C-KIT expression and the tumor grade was proved in some studies (Simon et al., 2004; Tsuda et al., 2005; Diallo et al., 2006; Shams and Shams, 2011), but not proved in others (Nalwoga et al., 2008; Amin et al. 2012). The last authors also did not find a positive correlation between C-KIT expression and patients’ age or the tumor size, which was significantly correlated with C-KIT in another study (Kim et al., 2008).
In this study, we found a nonsignificant association between HER-2/neu, ER, and C-KIT expression. However, C-KIT was significantly decreased in PR-positive IDC (P=0.009). Diallo et al. (2006) and Amin et al. (2012) found that C-KIT expression was significantly lower in ER-positive or PR-positive cases. Also, Shams and Shams (2011) found that the frequency of C-KIT immunoreactivity was 75% in triple-negative breast cancer. In addition, Tsuda et al. (2005) found marginal significance between HER-2/neu-overexpressing and C-KIT-overexpressing cases, However, Diallo et al. (2006) found that C-KIT expression was strongly associated with HER-2 positivity, a finding that was not observed in this study. The reason for this difference is still unclear and might be a sign of dedifferentiation with a different meaning than C-KIT expression in the normal breast epithelium or benign breast lesions (Diallo et al., 2006).
The loss of C-KIT may be involved at early stages of breast cancer development. C-KIT expression in breast cancer may be associated with negative lymph node metastasis and loss of progesterone receptors. Further studies are required to clarify the active mechanism of C-KIT proto-oncogene production in human breast and to investigate the efficiency of C-KIT in the diagnosis of breast adenoid cystic carcinoma and the possible beneficial effects of C-KIT inhibitor therapy in C-KIT-positive breast cancers.
There are no conflicts of interest.
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