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.

Transcriptionally inducible Pleckstrin homology-like domain, family A, member 1, attenuates ErbB receptor activity by inhibiting receptor oligomerization

“…Finally, we examined the biological function of PHLDA1 in the MCF-7 system. In a previous study, it was shown that HRGstimulated MCF-7 cells undergo cellular differentiation as indicated by lipid accumulation (18,39). We confirmed that HRG treatment induced lipid accumulation (Fig.…”

“…We slightly modified the previously published method (39) as follows: 0.4 ϫ 10 5 cells/well were seeded in standard 24-well plates. Culture medium was replaced with serum-free medium 24 h prior to stimulation, and cells were stimulated with 10 nM HRG.…”

Defined spatiotemporal features of RAS-ERK signals dictate cell fate in MCF-7 mammary epithelial cells

“…A second possibility is that additional signals are requited for HRG-induced differentiation. In this respect, it was shown that HRG-evoked differentiation of MCF-7 cells requires PI-3K activation ( Volinsky et al. , 2015 ).…”

MicroRNA-421-targeted PDCD4 regulates breast cancer cell proliferation

“…However, the molecular mechanisms of BC remain to be fully elucidated. It is well known that an accumulation of hereditary and epigenetic changes, including oncogene activation, tumor suppressor gene inactivation ( 6 ), changes in intercellular complex signal networks, microenvironment ( 7 , 8 ) and epigenetic changes ( 9 , 10 ) contribute to the formation of malignant tumors. An increasing number of studies have indicated that epigenetic changes may represent important events in the pathogenesis of BC ( 11 - 13 ), and that gene silencing at the post-transcriptional level may be an important epigenetic change ( 14 , 15 ).…”