Remodeling of the mammary epithelial cell lipidome by SETD7 and its significance to breast cancer: a lipidomic approach

• Autor(a) principal: Góis, André Ricardo Barbosa
• Data de Publicação: 2021
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10773/33824
• topic: Differentiation; Mammary gland; Lipids; Metabolism; SETD7; Breast cancer; Lipidomics; Phospholipidome; LC-MS

Lipids are structural components of cell membranes, as well as important signaling mediators. The membrane’s lipid composition dictates its fluidity, and consequently the cell’s proliferative, migratory, and secretory potential. When lactation is induced on the mammary gland, mammary epithelial cells differentiate into a specialized secretory state, and their lipidome accompanies this transition, to cope with the increased lipidic demand for lactation. It has been reported that the lipidome of breast cancer cells with a worse disease prognosis is resemblant to that of proliferative undifferentiated mammary epithelial cells. Therefore, it is imperative to study the mechanisms controlling the lipid metabolism on these cells and the factors involved in the transition from a proliferative to a functionally differentiated lipidomic phenotype. SETD7 is a methyltransferase that modulates the expression of several transcription factors related to biological processes with relevance for cancer, including cell proliferation and chromatin remodelling. Previous results showed that inhibition of SETD7 on HC11 mammary epithelial cells led to an abnormal phenotype on differentiated cells, resembling that of undifferentiated cells, suggesting a role for SETD7 in epithelial differentiation as well. SETD7 is also known to target key players of lipid metabolism like XBP1 and RORα2. In this study, we inhibited the activity of SETD7 on HC11 mammary epithelial cells to study the effect of this shut down on the lipidome and relate the differences to the profile presented during differentiation. Mass spectrometry and thin-layer chromatography were used to study the lipidome of these cells. A decrease in phosphatidylcholine and synthesis of phosphatidylethanolamine, longer and more unsaturated fatty acids, are observed during differentiation to facilitate secretion. These adaptations seemed to be impaired by the inhibition of SETD7. This inhibition led to a lipid profile suggestive of higher proliferative potential, characteristic of undifferentiated cells and cancer cells with metastatic potential. In sum, when combined with previous observations, these results suggest not only that SETD7 has an important modulating role in the differentiation of MEC, but that its activity is important for lipid homeostasis and the adaptation to the demands of lactation.