In the female population, breast cancer is the second cause of cancer- related deaths, behind the biggest killer, lung cancer. There are different treatment options for breast cancer patients, including endocrine agents, the ErbB2 receptor targeted antibody, trastuzumab, as well as standard chemotherapeutics. Despite improvement in response to each of these options, likely related to early detection and better treatment, once a primary tumor has metastasized, it is essentially incurable. Thus, studies of the mechanisms and proteins that contribute to metastasis are of utmost importance for increasing the anti-cancer arsenal of drugs. In my lab we are working on breast cancer metastasis with our goal being to uncover novel protein players essential for this process. We discovered the protein Memo (mediator of ErbB2 driven cell motility) while screening for ErbB2 interacting proteins with essential roles in cancer cell motility. Memo is encoded by a gene that found in all kingdoms of life (bacteria, fungi and mammals) and is highly conserved. The function of Memo was not known in any species when we uncovered it in our initial screen. As the name suggests, Memo is important for cancer cell motility induced, not only by ErbB2 activation, but also by activation of other receptors such as the fibroblast growth factor receptor (FGFR) and the platelet derived growth factor receptor (PDGFR), suggesting that Memo has a general role in migration induced by extracellular cues.
Based on these initial results, using funds generously supplied by the SNF, we initiated a large project with three main goals: 1) To test if Memo has an essential role in metastasis, using in vivo models of breast cancer growing in mice; 2) To uncover the normal physiological role of Memo, using mouse genetics combined with biochemical approaches; 3) To use the model organism S. cerevisiae to characterize the Memo-homologue, Mho1, and to investigate its function in yeast. We have been relatively successful in all three goals, although as is usual for science, our results have raised many more questions, which is so aptly summed up in the quote “Science is an endless frontier” from the famous engineer Vannevar Bush.
I will briefly summarize our most important results. 1) We have found that Memo is essential for in vivo metastasis formation. For these studies we used a technology which allows the knock-down of the Memo protein in breast cancer cell lines, termed KD cells. The Memo KD tumor cells and the parental cells that express Memo were injected into the mammary gland of NOD/SCID mice where they both grew into tumors. Importantly, the Memo KD tumors gave rise to significantly fewer lung metastases. These results suggest that Memo is important for tumor cell migration and in the formation of metastasis. We have partially elucidated the molecular mechanisms responsible for these effects. 2) To uncover Memo’s normal physiological role, full-body Memo knock-out (KO) mice were generated. Surprisingly, these animals display rapid onset of a premature aging phenotype, including small stature, hair graying, hair loss, and curvature of the back. They also exhibit increased insulin sensitivity and alteration of vitamin D metabolism, with increased levels of serum vitamin D and calcium. The features of the Memo KO mice recapitulate some features of mice lacking FGF23 or its receptor, Klotho. Since this ligand and its receptor have important roles in the kidney, controlling circulating level of Vitamin D, we looked for a role for Memo down-stream of FGFR. For these studies we used cell culture models and examined the effects of FGF in Memo WT and KO cell lines. Our results show that Memo does have important function downstream of FGF-induced signaling; in the absence of Memo the strength and duration of FGFR signaling is impaired. Whether Memo plays a role in normal aging in humans awaits further studies that would have to be done in collaboration with population geneticists. 3) In yeast, MHO1 expression is induced by stress conditions. Since invasive growth is also stress-induced, we tested Mho1’s role in this response. We found that overexpression of Mho1 blocked the invasive ability of yeast cells, suggesting that Mho1 might be acting in a dominant negative manner. Thus, considering the results in yeast and in human cancer cells, a role for Memo in cell motility/invasion appears to be conserved across species.