High nuclear phosphorylated extracellular signal-regulated kinase expression associated with poor differentiation, larger tumor size, and an advanced stage of breast cancer

Abstract

Extracellular signal-regulated kinase (ERK1/2) is implicated in the malignant behavior of breast cancer cells. However, previous clinical-pathological studies have shown that expression of activated/phosphorylated ERK1/2 is not associated with enhanced proliferation and invasion of mammary carcinomas. ERK1/2 is expressed in the cytoplasm, and activated/phosphorylated ERK1/2 translocates to the nucleus. The aim of this study is to evaluate nuclear phosphorylated ERK1/2 as a biomarker for breast cancer prognosis. The clinical-pathological relation of cytoplasmic/nuclear phosphorylated ERK1/2 was analyzed in 105 surgically resected breast cancer specimens by immunohistochemistry with tissue microarray. The results showed that non-neoplastic breast tissue mainly showed faint phosphorylated ERK1/2 staining. No statistically significant association was found between the level of cytoplasmic phosphorylated ERK1/2 expression and the clinical features of the disease. High nuclear phosphorylated ERK1/2 expression was associated with high grade (poor differentiation, p = 0.010), high T status (larger tumor size, p = 0.033), and an advanced stage (p = 0.018) of the disease. Thus, nuclear phosphorylated ERK1/2 is associated with enhanced proliferation and invasion of mammary carcinomas and may be a biomarker for breast cancer prognosis and the determination of therapeutic strategies.

Reduced miR-550a-3p leads to breast cancer initiation, growth, and metastasis by increasing levels of ERK1 and 2

“…Several survival analyses indicate that higher ERK1/2 expression or activity in primary breast tumors is prognostic for poorer overall survival or relapse-free survival of patients [ 11 - 13 , 17 , 18 ]. Higher nuclear p-ERK1/2 has also been associated with more aggressive behaviors of breast cancer such as higher pathological grade and larger tumor size [ 16 ], in agreement with our finding that nuclear p-ERK1/2 was the dominantly stained pattern in our primary tumor and metastatic breast cancer specimens. Moreover, the expression and activity of ERK1/2 also impact the patients’ therapeutic responses [ 36 , 37 ].…”

“…In contrast, ERKs1 and 2, and their active phosphorylated forms (p-ERK1/2) were present in higher levels in metastatic breast cancer than primary breast cancer, and at very low levels in benign breast diseases (Figure 1C ). Nuclear p-ERK1/2, reported to be the most deleteriously stained pattern, was dominantly observed in primary and metastatic breast cancer [ 16 ]. As shown in Supplementary Table S2 , miR-550a-3p ( p < 0.001) was significantly lower in breast cancer samples than benign breast disease samples; ERK1 ( p = 0.036), ERK2 ( p = 0.011) and p-ERK1/2 ( p = 0.007), on the other hand, were significantly increased in the breast cancer samples relative to benign breast disease samples.…”

“…Aberrant hyperactivation of ERK1 and 2 and their downstream targets/effectors is observed during cancer initiation, progression, and recurrence in a large subset of breast cancer [ 3 , 5 , 6 ]. Higher levels of ERKs1 and 2 and their active phosphorylated forms is significantly associated with increased risk of breast cancer incidence [ 14 , 15 ] as well as poorer tumor differentiation, and larger tumor size [ 16 ], characteristic features of worse cancer progression or prognosis [ 11 , 17 , 18 ]. However, conflicting results have been reported [ 19 , 20 ].…”

Snail Promotes Epithelial Mesenchymal Transition in Breast Cancer Cells in Part via Activation of Nuclear ERK2

“…These findings correspond to a recent communication that analyzed p-ERK expression in patient tumors [26]. High levels of p-ERK were associated with poor prognosis based on poor differentiation, larger tumor sizes, and higher stages of breast cancer.…”

Clinicopathological and prognostic significance of mitogen-activated protein kinases (MAPK) in breast cancers

“…The function of MAPKs in breast cancer (BC) is complex due to different responses they modulate and their interaction with different pathways [ 9 – 11 ]. MAPKs have been investigated in BC including their interaction with oestrogen receptor (ER) and HER2; however, conflicting results were reported and the exact role of MAPKs in BC and their interaction with ER and HER2 remain to be determined [ 12 – 14 ].…”