The relationship between the expression levels of matrix metalloproteinase-2 (MMP-2) and MMP-9 and breast cancer prognosis was studied. Two breast cancer cell lines (MDA-MB-231 and MCF-7) and one human normal breast cell line (HS578Bst) were investigated. Fluorescence real-time reverse transcription-polymerase chain reaction (RT-PCR) and western blotting were used to detect cellular mRNA and protein MMP-2 and MMP-9 expression levels. Breast cancer tissue samples from 80 patients and tumor-adjacent normal tissue samples from 40 patients were collected, and MMP-2 and MMP-9 expression in these samples were examined using immunohistochemistry (IHC). The relationship of MMP-2 and MMP-9 expression levels with breast cancer patient clinicopathological parameters and prognosis was analyzed. RT-PCR and western blot results showed that MMP-2 and MMP-9 mRNA and protein expression levels were significantly higher in MDA-MB-231 and MCF-7 cells than in HS578Bst cells. A high expression of MMP-2 and MMP-9 was found in 83.75% (67/80) and 78.75% (63/80) of breast cancer tissue samples, respectively. MMP-2 and MMP-9 expression in breast cancer tissues were significantly different from that in tumor-adjacent normal tissues (p<0.01). MMP-2 and MMP-9 expression levels in breast cancer tissues were correlated with lymph node metastasis and tumor staging. Single factor survival analysis showed that MMP-2 and MMP-9 were factors influencing breast cancer prognosis. MMP-2 and MMP-9 are highly expressed in breast cancer tissues and are closely related to lymph node metastasis and tumor staging. MMP-2 and MMP-9 can be used as reference indices for guiding breast cancer prognosis and treatment.

https://www.spandidos-publications.com/10.3892/ol.2017.6924/download

The relationship between MMP-2 and MMP-9 expression levels with breast cancer incidence and prognosis.

Cancer, a complex yet common disease, is caused by uncontrolled cell division and abnormal cell growth due to a variety of gene mutations. Seeking effective treatments for cancer is a major research focus, as the incidence of cancer is on the rise and drug resistance to existing anti-cancer drugs is major concern. Natural products have the potential to yield unique molecules and combinations of substances that may be effective against cancer with relatively low toxicity/better side effect profile compared to standard anticancer therapy. Drug discovery work with natural products has demonstrated that natural compounds display a wide range of biological activities correlating to anticancer effects. In this review, we discuss formononetin (C16H12O4), which originates mainly from red clovers and the Chinese herb Astragalus membranaceus. The compound comes from a class of 7-hydroisoflavones with a substitution of methoxy group at position 4. Formononetin elicits antitumorigenic properties in vitro and in vivo by modulating numerous signaling pathways to induce cell apoptosis (by intrinsic pathway involving Bax, Bcl-2, and caspase-3 proteins) and cell cycle arrest (by regulating mediators like cyclin A, cyclin B1, and cyclin D1), suppress cell proliferation [by signal transducer and activator of transcription (STAT) activation, phosphatidylinositol 3-kinase/protein kinase-B (PI3K/AKT), and mitogen-activated protein kinase (MAPK) signaling pathway], and inhibit cell invasion [by regulating growth factors vascular endothelial growth factor (VEGF) and Fibroblast growth factor 2 (FGF2), and matrix metalloproteinase (MMP)-2 and MMP-9 proteins]. Co-treatment with other chemotherapy drugs such as bortezomib, LY2940002, U0126, sunitinib, epirubicin, doxorubicin, temozolomide, and metformin enhances the anticancer potential of both formononetin and the respective drugs through synergistic effect. Compiling the evidence thus far highlights the potential of formononetin to be a promising candidate for chemoprevention and chemotherapy.

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Formononetin: A Review of Its Anticancer Potentials and Mechanisms

Formononetin-induced oxidative stress abrogates the activation of STAT3/5 signaling axis and suppresses the tumor growth in multiple myeloma preclinical model

Formononetin, an isoflavone, is extracted from various medicinal plants and herbs, including the red clover (Trifolium pratense) and Chinese medicinal plant Astragalus membranaceus. Formononetin’s antioxidant and neuroprotective effects underscore its therapeutic use against Alzheimer’s disease. Formononetin has been under intense investigation for the past decade as strong evidence on promoting apoptosis and against proliferation suggests for its use as an anticancer agent against diverse cancers. These anticancer properties are observed in multiple cancer cell models, including breast, colorectal, and prostate cancer. Formononetin also attenuates metastasis and tumor growth in various in vivo studies. The beneficial effects exuded by formononetin can be attributed to its antiproliferative and cell cycle arrest inducing properties. Formononetin regulates various transcription factors and growth-factor-mediated oncogenic pathways, consequently alleviating the possible causes of chronic inflammation that are linked to cancer survival of neoplastic cells and their resistance against chemotherapy. As such, this review summarizes and critically analyzes current evidence on the potential of formononetin for therapy of various malignancies with special emphasis on molecular targets.

https://www.mdpi.com/2072-6694/11/5/611/pdf

Focus on Formononetin: Anticancer Potential and Molecular Targets.

Exploring the pharmacological mechanism of Yanghe Decoction on HER2-positive breast cancer by a network pharmacology approach.

Formononetin is a naturally existing isoflavone, which can be found in the roots of Astragalus membranaceus, Trifolium pratense, Glycyrrhiza glabra, and Pueraria lobata. It was found to be associated with inhibition of cell proliferation and cell cycle progression, as well as induction of apoptosis in various cancer cell lines. However, the effect of formononetin on breast cancer cell metastasis remains unclear. In this study, we examined the effect of formononetin on the migration and invasion of breast cancer cells MDA-MB-231 and 4T1 in vitro and in vivo. Our data demonstrated that formononetin did not effectively inhibit the cell viability of MDA-MB-231 and 4T1 in 24 h with the concentration lower than 160 μmol/l. When treated with nontoxic concentration of formononetin, the migration and invasion of MDA-MB-231 and 4T1 cells were markedly suppressed by wound healing assay, chamber invasion assay, and in vivo mouse metastasis model. In vitro, formononetin reduced the expression of matrix metalloproteinase-2 (MMP-2), MMP-9 and increased the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2. Furthermore, the immunoﬂuorescence and immunoblotting assays indicated that formononetin was very effective in suppressing the phosphorylation of Akt and PI3K. Collectively, these results suggest that formononetin inhibited breast cancer cell migration and invasion by reducing the expression of MMP-2 and MMP-9 through the PI3K/AKT signaling pathway. These findings demonstrate a potentially new therapeutic strategy of formononetin as anti-invasive agent for breast cancer.

/pdf/formononetin-inhibits-migration-and-invasion-of-mda-mb-231-2xn17jslq1.pdf

Formononetin Inhibits Migration and Invasion of MDA-MB-231 and 4T1 Breast Cancer Cells by Suppressing MMP-2 and MMP-9 Through PI3K/AKT Signaling Pathways

R Zhou

Papers

Formononetin Inhibits Migration and Invasion of MDA-MB-231 and 4T1 Breast Cancer Cells by Suppressing MMP-2 and MMP-9 Through PI3K/AKT Signaling Pathways