Overexpression of Lox in triple-negative breast cancer.

BACKGROUND: Triple negative breast cancer (TNBC) accounts for approximately 15% of breast cancers. It is associated with a poor prognosis and typically earlier onset of metastasis in comparison with other breast cancer subtypes. Since TNBC lacks the expression of estrogen and progesterone receptors and Her2 status is also negative, there is currently no target that can be used for systemic therapy. Epithelial-mesenchymal transition (EMT) plays an important role in tumor progression and metastasis. In this study, we examined a subset of EMT markers consisting of Snail, Twist-1 and Lox in TNBC and non-TNBC breast cancer subtypes and analyzed their expression pattern in regard to subtype, clinico-pathological parameters and prognosis. EXPERIMENTAL DESIGN: We analyzed 659 breast cancer samples from two tissue microarrays. Breast cancer samples were categorized into two groups according to hormone receptor expression and Her2 status (n = 146 were triple negative, n = 513 were non triple-negative). Immunohistochemical expression of Snail, Twist-1 and Lox was semi-quantitatively analyzed using a three-tiered (weak-moderate-strong) scoring system. Results were statistically analyzed and correlated to clinico-pathological parameters and overall survival. RESULTS: Strong overexpression of Lox was significantly higher in triple negative breast cancers when compared to non triple-negative breast cancers (p < 0.001). No difference was seen between the groups regarding Snail and Twist expression (p > 0.05). In addition, Lox expression was significantly stronger in poorly differentiated (G3) breast cancers (p < 0.001 for Lox). CONCLUSIONS: The EMT marker Lox has a differential expression pattern in breast cancer, being significantly overexpressed in triple negative breast cancers. We could not link this expression to prognosis, however, this marker might be explored in future studies as possible target for systemic therapy of TNBC.

Differential expression of epithelial­mesenchymal transition and stem cell markers in intrinsic subtypes of breast cancer.

The transcription factors SLUG and SOX9 have been shown to define mammary stem cell state. Similarly, epithelial­mesenchymal transition (EMT) markers (E-Cadherin, mTOR) have been shown to play a role in tumor-progression and metastatic potential in breast cancer. Finally, SOX10 is known to be expressed in breast cancer as well. The overexpressions of EMT and stem cell markers have been shown to correlate with poor overall survival. In this study, we examined whether the expression of these markers correlates with intrinsic subtypes of breast cancer and whether there is a prognostic difference in their expression-profile. We analyzed 617 breast cancer samples from two tissue micro arrays. Breast cancer samples were categorized into three groups according to hormone receptor expression and HER2-status as Luminal A/B, HER2-positive, and triple negative subgroup. Immunohistochemical expressions of SLUG, SOX9, SOX10, E-Cadherin, and mTOR were semi-quantitatively analyzed using a two-tiered and three-tiered scoring system in which cytoplasmic and nuclear stains were considered. Strong nuclear expression of SLUG was observed preferentially in triple negative but not in Luminal A/B or HER2-positive cases (24 vs. 3 and 0 %, p < 0.001). Loss of SOX9 in the nuclear stain was less frequent in triple negative than in Luminal A/B or HER2-positive cases (4 vs. 9 vs. 13 %, p < 0.001). Expression of nuclear SOX10 was lower in triple negative than in Luminal A/B and HER2-positive cases (67 vs.78 and 79 %, p = 0.012). E-Cadherin loss was observed only in Luminal A/B tumors (p = 0.016), no difference in the mTOR expression was seen between any of the three groups. No correlation to conventional histopathological-parameters or stage could be established in our cohort. Our study shows an inversed preferential nuclear expression of SLUG, SOX10, and SOX9 in triple negative and non-triple negative cases. This information is important in understanding the biology of triple negative breast cancer, also in terms of future studies dealing with targeted therapies based on the alterations of EMT and stem cell markers.