Transcription factors zeb1, twist and snai1 in breast carcinoma

Abstract

Background: Epitheliomesenchymal transition (EMT) is the process where cancer cells attain fibroblastic features and are thus able to invade neighboring tissues. Transcriptional factors zeb1, snai1 and twist regulate EMT.

Methods: We used immunohistochemistry to investigate the expression of zeb1, twist and snai1 in tumor and stromal compartments by in a large set of breast carcinomas. The results were compared with estrogen and progesterone receptor status, HER2 amplification, grade, histology, TNM status and survival of the patients.

Results: Nuclear expression for twist was seen in the epithelial tumor cell compartment in 3.6% and for snai1 in 3.1% of the cases while zeb1 was not detected at all in these areas. In contrast, the tumor stromal compartment showed nuclear zeb1 and twist expression in 75% and 52.4% of the cases, respectively. Although rare, nuclear expression of twist in the epithelial tumor cell compartment was associated with a poor outcome of the patients (p = 0.054 log rank, p = 0.013, Breslow, p = 0.025 Tarone-Ware). Expression of snai1, or expression of zeb1 or twist in the stromal compartment did not have any prognostic significance. Furthermore, none of these factors associated with the size of the tumors, nor with the presence of axillary or distant metastases. Expression of zeb1 and twist in the stromal compartment was positively associated with a positive estrogen or progesterone receptor status of the tumors. Stromal zeb1 expression was significantly lower in ductal in situ carcinomas than in invasive carcinomas (p = 0.020). Medullary carcinomas (p = 0.017) and mucinous carcinomas (p = 0.009) had a lower stromal expression of zeb1 than ductal carcinomas. Stromal twist expression was also lower in mucinous (p = 0.017) than in ductal carcinomas.

Conclusions: Expression of transcriptional factors zeb1 and twist mainly occur in the stromal compartment of breast carcinomas, possibly representing two populations of cells; EMT transformed neoplastic cells and stromal fibroblastic cells undergoing activation of zeb1 and twist due to growth factors produced by the tumor. However, epithelial expression of twist was associated with a poor prognosis, hinting at its importance in the spread of breast carcinoma.

Figure 1

Expression of zeb1 in breast carcinoma. Strong nuclear expression is found in the stromal compartment while cells in the epithelial compartent are negative. The positive nuclei in stroma, however, show variation in size and display conspicuous nucleoli.

Figure 2

Expression of twist in breast carcinoma. In this case of a breast carcinoma, strong nuclear expression of twist is found in nuclei of the epithelial cell compartment of the cells.

Figure 3

Expression of snai1 in breast carcinoma. Tumor cells show nuclear expression in the epithelial compartment while fusiform stromal cells are negative. There is some cytoplasmic positivity in both tumor and stromal cells.

Figure 4

Expression of twist in breast carcinoma. In this case nuclear expression is found in the stromal compartment while epithelial tumor cells are negative.

Figure 5

Patients with tumors expressing nuclear twist positivity in the epithelial compartment had a poorer survival (p = 0.054 log rank, p = 0.013, Breslow, p = 0.025 Tarone-Ware).