title: Signalling mechanisms regulating phenotypic changes in breast cancer cells.
abstract: In MCF-7 breast cancer cells epidermal growth factor (EGF) induces cell proliferation, whereas heregulin (HRG)/neuregulin (NRG) induces irreversible phenotypic changes accompanied by lipid accumulation. Although these changes in breast cancer cells resemble processes that take place in the tissue, there is no understanding of signalling mechanisms regulating it. To identify molecular mechanisms mediating this cell-fate decision process, we applied different perturbations to pathways activated by these growth factors. The results demonstrate that phosphoinositide 3 (PI3) kinase (PI3K) and mammalian target of rapamycin (mTOR) complex (mTORC)1 activation is necessary for lipid accumulation that can also be induced by insulin, whereas stimulation of the extracellular-signal-regulated kinase (ERK) pathway is surprisingly dispensable. Interestingly, insulin exposure, as short as 4 h, was sufficient for triggering the lipid accumulation, whereas much longer treatment with HRG was required for achieving similar cellular response. Further, activation patterns of ATP citrate lyase (ACLY), an enzyme playing a central role in linking glycolytic and lipogenic pathways, suggest that lipids accumulated within cells are produced de novo rather than absorbed from the environment. In the present study, we demonstrate that PI3K pathway regulates phenotypic changes in breast cancer cells, whereas signal intensity and duration is crucial for cell fate decisions and commitment. Our findings reveal that MCF-7 cell fate decisions are controlled by a network of positive and negative regulators of both signalling and metabolic pathways.
authors: *Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Republic of Ireland.
authors: Natalia
authors: N
authors: Volinsky
authors: *Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Republic of Ireland.
authors: Cormac J
authors: CJ
authors: McCarthy
authors: *Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Republic of Ireland.
authors: Alex
authors: A
authors: von Kriegsheim
authors: *Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Republic of Ireland.
authors: Nina
authors: N
authors: Saban
authors: †Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences (IMS), Tsurumi-ku, Yokohama, Kanagawa, Japan.
authors: Mariko
authors: M
authors: Okada-Hatakeyama
authors: *Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Republic of Ireland.
authors: Walter
authors: W
authors: Kolch
authors: *Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Republic of Ireland.
authors: Boris N
authors: BN
authors: Kholodenko
mesh_terms: D001275:ATP Citrate (pro-S)-Lyase / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D061986:MCF-7 Cells; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D001275:ATP Citrate (pro-S)-Lyase; D007328:Insulin; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; C094131:NRG1 protein, human
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