Proliferation of human mammary cancer cells exposed to 27-hydroxycholesterol

Abstract

Abstract. the aim of the present study was to identify the possible mechanisms by which certain estradiol receptor (Er)-positive mammary tumor cells remain resistant to treatment with anti-estrogens or inhibitors of local estradiol (E 2 ) production. to this end, we compared the proliferative effects on mammary cancer cells of the novel selective Er modulator 27-hydroxycholesterol (27Ohc) to those of E 2 , and evaluated their inhibition by ici 182,780 (ici). analysis of the effects on the cell cycle of 27Ohc and E 2 in the absence or presence of ici was conducted. in Er-positive mammary tumor cells, we detected the blocking of 27Ohc proliferationstimulatory activity by simvastatin, as well as the inhibition of E 2 -stimulated proliferation by an α-fetoprotein-derived cyclic nonapeptide. the effects reported herein may be extrapolated to infiltrating mammary cancer, where the activity of local macrophages may stimulate tumor growth. We suggest that increased breast cancer growth in obese patients may be related to increased 27Ohc circulatory levels.

27-hydroxycholesterol and the expression of three estrogen-sensitive proteins in MCF7 cells

“…The same groups reported later on the detrimental activity of 27OHC on bone homeostasis (3,4). The proliferation of various ER-positive mammary cancer cell lines is also affected by 27OHC, as demonstrated by DuSell et al (2) and by us (5). Remarkably, the proliferation rate of nontumorigenic mammary MCF10 cells are not affected by the exposure to micromolar concentrations of 27OHC (5).…”

“…The proliferation of various ER-positive mammary cancer cell lines is also affected by 27OHC, as demonstrated by DuSell et al (2) and by us (5). Remarkably, the proliferation rate of nontumorigenic mammary MCF10 cells are not affected by the exposure to micromolar concentrations of 27OHC (5). Recently, we have demonstrated that the exposure of ER-positive epithelial mammary tumor cells to 2 µM 27OHC for longer than 48 h triggers their transition into a mesenchymal phenotype (6).…”

“…In our earlier report we showed that MCF7 cells undergoing the 27OHC-triggered EMT displayed a persistently activated EGFR2 at the plasma membrane with increased traslocation of pERK into the cell nucleus; interestingly, these cells did not exhibit variations in cell death rates by Annexin V/PI labeling (6). In contrast to the non-genomic mitogenic estradiol effects on MCF7 cells, where just a transient stimulation of EGFR2 is observed (5), the exposure to 27OHC caused permanent activation of this membrane receptor. As mentioned in our previous study, 27OHC-triggered EGFR2 activation is not related to the secretion of matrix metalloproteinases (MMPs) nor to the trimming and release of HB-EGF (5).…”

“…In contrast to the non-genomic mitogenic estradiol effects on MCF7 cells, where just a transient stimulation of EGFR2 is observed (5), the exposure to 27OHC caused permanent activation of this membrane receptor. As mentioned in our previous study, 27OHC-triggered EGFR2 activation is not related to the secretion of matrix metalloproteinases (MMPs) nor to the trimming and release of HB-EGF (5). Instead, the most important visible signals for the ongoing EMT were the marked evanescence of E-cadherin, the notorious cellular re-allocation of β-catenin and the permanent activation of EGFR2 (6).…”

The cholesterol metabolite 27-hydroxycholesterol regulates p53 activity and increases cell proliferation via MDM2 in breast cancer cells

“…Thus, fluctuations in 27-OHC may modulate ER and potentially contribute to the pathogenesis of ER+ breast cancers. While it has been established that 27-OHC is an endogenous selective ER modulator (SERM) and that it exacerbates breast cancer pathophysiology [5, 9, 10], its role in molecular events following ER activation in the context of breast cancer pathogenesis is not fully understood.…”