EPHB6 augments both development and drug sensitivity of triple-negative breast cancer tumours

Abstract

Triple-negative breast cancer (TNBC) tumours that lack expression of oestrogen, and progesterone receptors, and do not overexpress the HER2 receptor represent the most aggressive breast cancer subtype, which is characterised by the resistance to therapy in frequently relapsing tumours and a high rate of patient mortality. This is likely due to the resistance of slowly proliferating tumour-initiating cells (TICs), and understanding molecular mechanisms that control TICs behaviour is crucial for the development of effective therapeutic approaches. Here, we present our novel findings, indicating that an intrinsically catalytically inactive member of the Eph group of receptor tyrosine kinases, EPHB6, partially suppresses the epithelial–mesenchymal transition in TNBC cells, while also promoting expansion of TICs. Our work reveals that EPHB6 interacts with the GRB2 adapter protein and that its effect on enhancing cell proliferation is mediated by the activation of the RAS-ERK pathway, which allows it to elevate the expression of the TIC-related transcription factor, OCT4. Consistent with this, suppression of either ERK or OCT4 activities blocks EPHB6-induced pro-proliferative responses. In line with its ability to trigger propagation of TICs, EPHB6 accelerates tumour growth, potentiates tumour initiation and increases TIC populations in xenograft models of TNBC. Remarkably, EPHB6 also suppresses tumour drug resistance to DNA-damaging therapy, probably by forcing TICs into a more proliferative, drug-sensitive state. In agreement, patients with higher EPHB6 expression in their tumours have a better chance for recurrence-free survival. These observations describe an entirely new mechanism that governs TNBC and suggest that it may be beneficial to enhance EPHB6 action concurrent with applying a conventional DNA-damaging treatment, as it would decrease drug resistance and improve tumour elimination.

Eph receptor signalling: from catalytic to non-catalytic functions

“…The protein expression level of EphB6 was also decreased in multiple cancers, including breast cancer [89], NSCLC [90] and colorectal cancer [91]. Moreover, downregulation of EphB6 promoted cancer metastasis [92][93][94], whereas restoration of EphB6 expression suppressed metastasis [90,94,95]. Thus, EphB6 has been proposed as a tumour suppressor.…”

“…Thus, EphB6 has been proposed as a tumour suppressor. Interestingly, while playing a role as a potential metastasis suppressor, EphB6 was recently reported to accelerate cell proliferation in triple-negative breast cancer (TNBC) cell lines [95]. These studies imply that at different stages of cancer progression, EphB6 can perform distinct functions, although other factors, such as cell types or receptor expression level, cannot be excluded.…”

Cataloguing the dead: breathing new life into pseudokinase research

“…The absence of structural information for EphA10 and EphB6 is balanced by a large amount of structural information for closely related canonical Eph kinase domains, which have been crystallized in ‘active‐like’ (closed) and ‘inactive‐like’ (open) enzymatic conformations that are ideal for modelling purposes . This is in addition to an evolving appreciation of the cellular mechanisms by which catalytic output from Eph kinase and pseudokinase complexes are potentially coordinated .…”

The catalytically defective receptor protein tyrosine kinase EphA10 promotes tumorigenesis in pancreatic cancer cells

“…Although EphB4 enhances invasiveness without EphB6, the combination of EphB4 and EphB6 suppresses invasiveness in breast cancer cells 7 . However, in triple‐negative breast cancer, EphB6 potentiates tumor initiation, promotes the maintenance of tumor‐initiating cell populations, and augments drug sensitivity 8 . Additionally, EphB6 overexpression, together with APC gene mutations, enhances proliferation, invasion, and metastasis in colorectal epithelial cells 9 …”