Old Players with a Newly Defined Function: Fra-1 and c-Fos Support Growth of Human Malignant Breast Tumors by Activating Membrane Biogenesis at the Cytoplasm

Abstract

A shared characteristic of tumor cells is their exacerbated growth. Consequently, tumor cells demand high rates of phospholipid synthesis required for membrane biogenesis to support their growth. c-Fos, in addition to its AP-1 transcription factor activity, is the only protein known up to date that is capable of activating lipid synthesis in normal and brain tumor tissue. For this latter activity, c-Fos associates to the endoplasmic reticulum (ER) through its N-terminal domain and activates phospholipid synthesis, an event that requires it Basic Domain (BD) (aa 139–159). Fra-1, another member of the FOS family of proteins, is over-expressed in human breast cancer cells and its BD is highly homologous to that of c-Fos with two conservative substitutions in its basic amino acids. Consequently, herein we examined if Fra-1 and/or c-Fos participate in growth of breast cancer cells by activating phospholipid synthesis as found previously for c-Fos in brain tumors. We found both Fra-1 and c-Fos over-expressed in >95% of human ductal breast carcinoma biopsies examined contrasting with the very low or undetectable levels in normal tissue. Furthermore, both proteins associate to the ER and activate phospholipid synthesis in cultured MCF7 and MDA-MB231 breast cancer cells and in human breast cancer samples. Stripping tumor membranes of Fra-1 and c-Fos prior to assaying their lipid synthesis capacity in vitro results in non-activated lipid synthesis levels that are restored to their initial activated state by addition of Fra-1 and/or c-Fos to the assays. In MDA-MB231 cells primed to proliferate, blocking Fra-1 and c-Fos with neutralizing antibodies blocks lipid-synthesis activation and cells do not proliferate. Taken together, these results disclose the cytoplasmic activity of Fra-1 and c-Fos as potential targets for controlling growth of breast carcinomas by decreasing the rate of membrane biogenesis required for growth.

FRA1 promotes squamous cell carcinoma growth and metastasis through distinct AKT and c-Jun dependent mechanisms

“…It is likely that a similar molecular paradigm contributes to cSCC which shares many similarities with HNSCC in pathogenesis [17]. Our findings are also in line with earlier studies linking cytoplasmic c-Fos and FRA1 to the synthesis of membrane lipid polyphosphoinositides including PIP1 and PIP2 [31, 32], components essential for PI3K activation. In agreement with a role of FRA1 in membrane lipid synthesis, FRA1 was located on the cell membrane of tumor marginal cells (Data not shown).…”

“…Nevertheless, little is known about the role of FRA1 and the mechanisms mediating its function in HNSCC. Recently, it has been shown that FRA1 acts outside the nucleus to regulate membrane lipid synthesis in an AP-1-independent manner [31, 32]. In this study, we demonstrate that gene silencing of FRA1 impaired growth and migration of multiple HNSCC cell lines.…”

The Catalytic Efficiency of Lipin 1β Increases by Physically Interacting with the Proto-oncoprotein c-Fos

“…We have already proved the involvement of Fra-1 in the proliferation of breast cancer cells by increasing phospholipid labeling (38). Here, we also confirmed that at least for PAP I, Fra-1 is able to increase enzyme activity as c-Fos does.…”

Integrative genomic analysis of interleukin-36RN and its prognostic value in cancer

“…It mediates the anti-apoptotic response to hypoxic conditions and contributes to resistance to chemo-and radiotherapy in colon cancer cells (37), while it influences pivotal regulators of cell proliferation, migration and survival involved in melanoma progression (38) as well as in the carcinogenesis of the respiratory epithelium (39). c-Fos has been found to be associated with lipid-and phospholipid synthesis in several cell types (40) and activates biogenesis in certain types of tumor cell to support tumor growth (41,42). c-Jun is a critical transcription factor involved in major cell-biological activities, including cell proliferation, apoptosis, angiogenesis and invasiveness by specific regulation of epidermal growth factor receptor, keratinocyte growth factor, cyclin D1, p53, proliferin and CD44 (43)(44)(45)(46).…”