Differential ability of formononetin to stimulate proliferation of endothelial cells and breast cancer cells via a feedback loop involving MicroRNA‐375, RASD1, and ERα

Abstract

For postmenopausal cardiovascular disease, long-term estrogen therapy may increase the risk of breast cancer. To reduce this risk, estrogen may be replaced with the phytoestrogen formononetin, but how formononetin acts on vascular endothelial cells (ECs) and breast cancer cells is unclear. Here, we show that low concentrations of formononetin induced proliferation and inhibited apoptosis more strongly in cultured human umbilical vein endothelial cells (HUVECs) than in breast cancer cells expressing estrogen receptor α (ERα) (MCF-7, BT474) or not (MDA-MB-231), and that this differential stimulation was associated with miR-375 up-regulation in HUVECs. For the first time, we demonstrate the presence of a feedback loop involving miR-375, ras dexamethasone-induced 1 (RASD1), and ERα in normal HUVECs, and we show that formononetin stimulated this feedback loop in HUVECs but not in MCF-7 or BT474 cells. In all three cell lines, formononetin increased Akt phosphorylation and Bcl-2 expression. Inhibiting miR-375 blocked these changes and increased proliferation in HUVECs, but not in MCF-7 or BT474 cells. In ovariectomized rats, formononetin increased uterine weight and caused similar changes in levels of miR-375, RASD1, ERα, and Bcl-2 in aortic ECs as in cultured HUVECs. In mice bearing MCF-7 xenografts, tumor growth was stimulated by 17β-estradiol but not by formononetin. These results suggest selective action of formononetin in ECs (proliferation stimulation and apoptosis inhibition) relative to breast cancer cells, possibly via a feedback loop involving miR-375, RASD1, and ERα. This differential effect may explain why formononetin may not increase the risk of postmenopausal breast cancer.

Potential mechanisms of Chinese Herbal Medicine that implicated in the treatment of COVID-19 related renal injury

“…In addition, astragaloside isoflavanthin can regulate the immune system and enhance the body's function of producing interferon ( Yang et al, 2014 ). Formononetin has pharmacological effects such as lowering blood pressure, regulating inflammatory responses and lipid metabolism ( Chen et al, 2018 ). Attractylone may inhibit apoptosis by regulating PI3K-AKT pathway and other mechanisms ( Liu et al, 2017 ).…”

The Effects of Trifolium pratense L. Sprouts’ Phenolic Compounds on Cell Growth and Migration of MDA-MB-231, MCF-7 and HUVEC Cells

“…There are many studies showing formononetin antiproliferative potential against different cancer cell lines [21], emphasizing its selective activity against ER-positive breast cancer cells, i.e., MCF-7, and the lack of effectiveness in the case of ER-negative MDA-MB-231 cells [22]. In spite of this, Chen et al demonstrated its proliferation inhibition and apoptosis induction in MCF-7 and MDA-MB-231 cells, with, however, lower efficiency against HUVECs [23]. Authors suggested that observed cellular selectivity was connected with presence of a feedback loop involving miR-375, ras dexamethasone-induced 1 (RASD1) and ERα in HUVECs, but not in MCF-7 cells.…”

Long intergenic non-protein-coding RNA 01446 facilitates the proliferation and metastasis of gastric cancer cells through interacting with the histone lysine-specific demethylase LSD1

“…RASD1 belonged to the Ras family is originally regarded as a dexamethasone-inducible gene, and its product is a receptor-independent activator of G-protein signal 33 , 34 . Although there are still some controversies regarding the roles RASD1 played in carcinogenesis, many studies revealed that RASD1 could serve as a tumor suppressor in diverse malignancies 35 – 38 .…”