Memo Is a Copper-Dependent Redox Protein with an Essential Role in Migration and Metastasis

Abstract

Memo is an evolutionarily conserved protein with a critical role in cell motility. We found that Memo was required for migration and invasion of breast cancer cells in vitro and spontaneous lung metastasis from breast cancer cell xenografts in vivo. Biochemical assays revealed that Memo is a copper-dependent redox enzyme that promoted a more oxidized intracellular milieu and stimulated the production of reactive oxygen species (ROS) in cellular structures involved in migration. Memo was also required for the sustained production of the ROS O2- by NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase 1 (NOX1) in breast cancer cells. Memo abundance was increased in >40% of the primary breast tumors tested, was correlated with clinical parameters of aggressive disease, and was an independent prognostic factor of early distant metastasis.

Influencing the Tumor Microenvironment: A Phase II Study of Copper Depletion Using Tetrathiomolybdate in Patients with Breast Cancer at High Risk for Recurrence and in Preclinical Models of Lung Metastases

“…Copper has emerged as an essential component of the metastatic process, and multiple preclinical studies have demonstrated that copper depletion decreases proliferation, blood vessel formation, tumor growth, and motility (11)(12)(13)(14)(15). Copper depletion may also reverse epithelial-mesenchymal transition (EMT) and downregulate expression of EMT-related genes, such as vimentin and fibronectin (16).…”

MEMO1 drives cranial endochondral ossification and palatogenesis

“…The similarity between the Memo1 ki/ki and F1-9-13FP mutant phenotypes further suggested that the ENU-induced mutation generated a null allele. We therefore assayed MEMO1 protein expression using a monoclonal antibody that recognizes the N-terminus of MEMO1 21 . Western blot analysis of protein isolated from E13.5 heads of either the F1-9-13FP mutants (Fig 3K) or Memo1 ki/ki mutants (Supplemental Fig 3) showed a complete absence of protein in both instances indicating that the ENU induced mutation likely generates a null allele.…”

“…Here we identify Memo1 , a gene that encodes a previously described receptor tyrosine kinase (RTK)-adapter molecule and reactive oxygen species (ROS) generating redox enzyme, as a novel effector in promoting bone ossification, most notably in the cranial base 21,22 . The importance of MEMO1 in craniofacial development was initially identified through our recessive ENU-based forward genetic screen.…”

“…In turn, lost or reduced signaling could ultimately lead to a reduction in expression of cartilage to bone promoting factors, such as MMP9 and MMP13, as has been described during ossification in EGFR mutants 70 . A second plausible model for how MEMO1 may promote ossification is through its ability to generate ROS, a recently identified biochemical function for MEMO1 in other contexts 21 , and a known mechanism driving endochondral ossification 71-73 . ROS production during endochondral ossification has been shown to promote chondrocyte maturation and eventual apoptosis during bone replacement 71-73 .…”

“…Here we report the phenotypic and molecular characterization of one mutant from this screen that displayed a combination of craniofacial defects including cleft secondary palate, a domed cranium, and cranial base defects. We identified the affected gene responsible for these defects as Memo1 (Mediator of Erbb2 Driven Cell Motility 1), which encodes a multi-functional protein originally linked with cell migration and metastasis in breast cancer 19-21 . Mice homozygous for a Memo1 null mutation have previously been shown to die beginning at E13.5, accompanied by severe vasculature defects 22 .…”