MEK5/ERK5 Signaling Suppresses Estrogen Receptor Expression and Promotes Hormone-Independent Tumorigenesis

Abstract

Endocrine resistance and metastatic progression are primary causes of treatment failure in breast cancer. While mitogen activated protein kinases (MAPKs) are known to promote ligand-independent cell growth, the role of the MEK5-ERK5 pathway in the progression of clinical breast carcinoma remains poorly understood. Here, we demonstrated increased ERK5 activation in 30 of 39 (76.9%) clinical tumor samples, as well as across breast cancer cell systems. Overexpression of MEK5 in MCF-7 cells promoted both hormone-dependent and hormone-independent tumorigenesis in vitro and in vivo and conferred endocrine therapy resistance to previously sensitive breast cancer cells. Expression of MEK5 suppressed estrogen receptor (ER)α, but not ER-β protein levels, and abrogated downstream estrogen response element (ERE) transcriptional activity and ER-mediated gene transcription. Global gene expression changes associated with upregulation of MEK5 included increased activation of ER-α independent growth signaling pathways and promotion of epithelial-to-mesenchymal transition (EMT) markers. Taken together, our findings show that the MEK5-ERK5 pathway mediates progression to an ER(−), mesenchymal and endocrine therapy resistant phenotype. Given the need for new clinical therapeutic targets, our results demonstrate the therapeutic potential of targeting the MEK5-ERK5 pathway in breast cancer.

ERK5 regulates tobacco smoke-induced urocystic epithelial-mesenchymal transition in BALB/c mice

“…ERK5 is a lesser-studied member of the MAPK family. Various reports have suggested a functional role for ERK5 in cancer oncogenesis, and ERK5 has been demonstrated to promote EMT (19)(20)(21); however, its specific role in EMT regulation has not yet been verified. Previous studies have indicated that ERK5 triggers the motility and invasive phenotype of cells (22)(23)(24).…”

“…Extracellular signal-regulated kinase (ERK) 5 is the least studied member of the mitogen-activated protein kinase (MAPK) family, and is implicated in important cellular processes, including gene expression, proliferation, apoptosis, angiogenesis, cell motility and differentiation (15)(16)(17)(18) (19)(20)(21) and triggers a motility and invasive phenotype of cells (22)(23)(24). Additional studies have suggested a differential regulatory role of ERK5 in EMT (25,26).…”

The MEK5/ERK5 signalling pathway in cancer: a promising novel therapeutic target

“…This led to the conclusion that patients with low ERK5 expression benefited from systemic treatments, whereas those with high ERK5 expression did not [29]. Regarding luminal tumours, MEK5/ERK5 signalling enhancement was associated with worse prognosis because of the contribution to endocrine treatment resistance [30] and progression to hormone-independent tumorigenesis [31].…”

“…However, multiple additional studies demonstrated that ERK5 activation in MCF-7, MDA-MB-468, MDA-MB-453, and SKBR3 breast cancer cell lines promoted resistance to therapy, migration, and invasion [31,34,40,41], thus supporting ERK5 signalling as a potential therapeutic target in breast cancer. Moreover, increased active ERK5 was found in 70-80% of human breast tumours compared with adjacent tissue, and ERK5 was activated in all brain metastasis Q3 detected [31,42].…”

The kinome associated with estrogen receptor-positive status in human breast cancer

“…However, the mechanisms leading to increased ERa expression during tumorigenesis are poorly understood. Interestingly, beside alterations in ER gene transcription (Muscat et al 2013), altered kinase expression affecting ERa protein stability has been suggested (Henrich et al 2003, Antoon et al 2013 and, therefore, highlights the potential link between phosphorylation and estrogen signaling.…”