Evaluation of the Expression of Amine Oxidase Proteins in Breast Cancer

Abstract

We aimed to evaluate the expression of amine oxidase proteins in breast cancer and their clinical implications. We performed immunohistochemical staining of amine oxidase proteins (LOX, lysyl oxidase, AOC3, amine oxidase, MAOA, monoamine oxidase A, MAOB, monoamine oxidase B). Based on their hormone receptors, such as estrogen receptor (ER) and progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), and Ki-67 immunohistochemical staining, breast cancer was divided into four molecular subtypes: luminal A, luminal B, HER-2 type, and triple-negative breast cancer (TNBC). Luminal A was observed in 380 cases (49.4%), luminal B in 224 (29.1%), HER-2 type in 68 (8.8%), and TNBC in 98 (12.7%). Stromal AOC3, MAO-A, and MAO-B expression varied according to molecular subtypes. Stromal AOC3 expression was high in luminal B and HER-2 type and MAO-A expression was high in luminal A and luminal B (p < 0.001). MAO-B expression was higher in TNBC than in other subtypes (p = 0.020). LOX positivity was associated with high histological grade (p < 0.001) and high Ki-67 labeling index (LI) (p = 0.009), and stromal AOC3 positivity was associated with high histological grade (p = 0.001), high Ki-67 LI (p < 0.001), and HER-2 positivity (p = 0.002). MAO-A positivity was related to low histological grade (p < 0.001), ER positivity, PR positivity (p < 0.001), and low Ki-67 LI (p < 0.001). In univariate analysis, MAO-A positivity was related to short disease-free survival in HER-2 type (p = 0.013), AOC3 negativity was related to short disease-free survival and overall survival in ER-positive breast cancer, PR-positive breast cancer, HER-2-negative breast cancer, and lymph node metastasis. In conclusion, the expression of amine oxidase proteins varies depending on the molecular subtype of breast cancer. Stromal AOC3 expression was high in luminal B and HER-2 type, and MAO-A expression was high in luminal A and luminal B.

Keywords: amine oxidase; breast cancer; estrogen receptor; human epidermal growth factor receptor 2; progesterone receptor.

Figure 1

Heat map of amine oxidase in breast cancer molecular subtype. LOX, lysyl oxidase, AOC3, amine oxidase, MAOA, monoamine oxidase A, MAOB, monoamine oxidase B, TNBC, triple negative breast cancer, S, stroma, green, positive, red, negative.

Figure 2

Differential expression of amine oxidase in different tumor subtypes. The expression of stromal AOC3, MAO-A, and MAO-B; high expression of stromal AOC3 in luminal B and HER-2-type breast cancers; and high MAO-A expression in luminal A and luminal B (p < 0.001). MAO-B expression was higher in TNBC than that in other proteins (p = 0.020).

Figure 3

Correlation between the expression of amine oxidase and clinicopathological characteristics. LOX positivity was associated with a high histological grade (p < 0.001) and high Ki-67 LI (p = 0.009). Stromal AOC3 positivity was associated with a high histological grade (p = 0.001), high Ki-67 LI (p < 0.001), and HER-2 positivity (p = 0.002). MAO-A positivity was associated with a low histological grade (p < 0.001), estrogen receptor (ER) positivity (p < 0.001), PR positivity (p < 0.001), and low Ki-67 LI (p < 0.001).

Figure 4

Functional analysis using STRING database. Using “Mutual Exclusivity” function, 3 significant gene pairs with mutually exclusive alteration were identified (ERBB2-PGR, AOC3-ERBB2, MKI67-ESR1) and 1 gene pair with concurrent alteration (AOC3-MAOA). The response to hormone stimulus (red) and the response to lipids (blue) include Lox and MAOB together with ESR1, suggestive of the presence of common activator of estrogen positive type of breast cancer.

Figure 5

Effect of the expression of amine oxidase on survival in breast cancer. MAO-A positivity was associated with short DFS in HER-2-type breast cancer (a) (p = 0.013), luminal A was associated with short OS (b) (p = 0.047). In ER-positive breast cancer, AOC3 negativity was associated with short DFS (c) and short OS (d) (p = 0.013 and p = 0.037, respectively). AOC3 negativity was associated with short DFS (e) and short OS (f) in PR-positive cancer (p = 0.028 and p = 0.012, respectively). In HER-2-negative breast cancer, AOC3 negativity was associated with short DFS (g) and short OS (h) (p = 0.026 and p = 0.037, respectively), and in the breast cancer showing lymph node metastasis, AOC3 negativity was associated with short DFS (i) and short OS (j) (p = 0.038 and p = 0.012, respectively).