MAP3K1 Expression is Associated With Progression and Poor Prognosis of Hormone Receptor-Positive, HER2-Negative Early-Stage Breast Cancer

Abstract

Background: MAP3K1 (Mitogen-Activated Protein Kinase Kinase Kinase 1) participates in the MAPK signal transduction pathway, responding to a number of mitogenic and metabolic stimuli, which may be related to breast cancer susceptibility and progression. In this study, we assessed whether overexpression of MAP3K1 promotes proliferation, migration, and invasion of breast cancer cells, and thus, affects the prognosis of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative early-stage breast cancer. Methods: Two HR-positive, HER2-negative breast cancer cell lines (MCF7 and T-47D), both overexpressing MAP3K1, were transfected with MAP3K1 short hairpin RNA plasmids (shMAP3K1) and their proliferation, migration, and invasion were examined. We assessed whether shMAP3K1 affects the cell cycle and levels of downstream signaling molecules, such as ERK and NF-κB, as well as sensitizes cells in both cell lines to chemotherapeutic and hormonal agents. A total of 161 patients with HR-positive, HER2-negative T1-T2 breast cancer and 0 to 3 nodal metastases were included. The expression of MAP3K1 and phospho (p)-ERK proteins was assessed by immunohistochemistry. Results: In both cell lines (MCF7 and T-47D), shMAP3K1 significantly reduced cell growth, migration, and invasion by downregulating MMP-9 and blocking the G2/M phase of the cell cycle and its regulatory molecule cyclin B1. Besides, shMAP3K1 downregulated ERK- and NF-κB-dependent gene transcription, and enhanced sensitivities of both cell lines to doxorubicin, docetaxel, and tamoxifen. Patients with MAP3K1 overexpression exhibited significantly poor 9-year disease-free survival (DFS; 72.6% vs. 88.5%, p = 0.022) and overall survival (OS; 83.8% vs. 96.2%, p = 0.012) relative to those without MAP3K1 overexpression. Furthermore, the p-ERK expression was significantly associated with MAP3K1 expression (p < 0.001) and correlated with a poor 9-year DFS (p = 0.033) and OS (p = 0.023). Conclusions: Our results indicate that overexpression of MAP3K1 plays a major role in poor prognosis of HR-positive, HER2-negative early-stage breast cancer.

Internalisation of integrin-bound extracellular matrix modulates invasive carcinoma cell migration

“…While α2 integrin expression correlates with poor overall survival and resistance to gemcitabine in high-stiffness matrices in pancreatic cancer 82 , poorly differentiated tumours were reported to express low levels of α2 integrin, while well-differentiated ones showed high levels of α2 integrin 83 . Consistent with our data showing a correlation between MAP3K1 levels and poor prognosis in PDAC patients, MAP3K1 expression correlates with progression and poor prognosis of hormone-receptor-positive, HER2-negative early-stage breast cancer patients 84 . Single-cell transcriptomes from matched primary tumours and metastasis from patient-derived xenograft models of breast cancer showed that metastasis displayed increased stress response signalling during metastatic progression 85 .…”

Uncovering the Anticancer Potential of Polydatin: A Mechanistic Insight

“…Sometimes, these CDKs and cyclins are upregulated or overexpressed leading to BC pathogenesis [ 68 ]. Upregulation of CDK2 and overexpression of cyclins E and B1 are observed in BC [ 69 , 70 ]. So, cell cycle arrest can be targeted for preventing BC progression.…”