Suppression of FOXM1 activities and breast cancer growth in vitro and in vivo by a new class of compounds

Ziegler, Yvonne; Laws, Mary J.; Guillen, Valeria Sanabria; Kim, Sung Hoon; Dey, Parama; Smith, Brandi Patrice; Gong, Ping; Bindman, Noah A.; Zhao, Yuechao; Carlson, Kathryn E.; Yasuda, Mayuri A.; Singh, Divya; Zhong, Li; El-Ashry, Dorraya; Madak-Erdoğan, Zeynep; Katzenellenbogen, John A.; Katzenellenbogen, Benita S.

doi:10.1038/s41523-019-0141-7

Cited by 64 publications

(102 citation statements)

References 51 publications

(60 reference statements)

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“…Because FOXM1 upregulation to high levels is particularly common in TNBC, we have examined the possibility of reducing TNBC aggressiveness and metastasis by inhibiting FOXM1 activity. We recently identified and characterized novel FOXM1 inhibitory compounds, and demonstrated their beneficial role in suppressing cancer cell proliferation and tumor growth through cell cycle blockade and the induction of apoptosis [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Suppression of Tumor Growth, Metastasis, and Signaling Pathways by Reducing FOXM1 Activity in Triple Negative Breast Cancer

Dey

Wang

Ziegler

et al. 2020

Cancers

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Metastasis-related complications account for the overwhelming majority of breast cancer mortalities. Triple negative breast cancer (TNBC), the most aggressive breast cancer subtype, has a high propensity to metastasize to distant organs, leading to poor patient survival. The forkhead transcription factor, FOXM1, is especially upregulated and overexpressed in TNBC and is known to regulate multiple signaling pathways that control many key cancer properties, including proliferation, invasiveness, stem cell renewal, and therapy resistance, making FOXM1 a critical therapeutic target for TNBC. In this study, we test the effectiveness of a novel class of 1,1-diarylethylene FOXM1 inhibitory compounds in suppressing TNBC cell migration, invasion, and metastasis using in vitro cell culture and in vivo tumor models. We show that these compounds inhibit the motility and invasiveness of TNBC MDA-MB-231 and DT28 cells, along with reducing the expression of important epithelial to mesenchymal transition (EMT) associated genes. Further, orthotopic tumor studies in NOD-SCID-gamma (NSG) mice demonstrate that these compounds reduce FOXM1 expression and suppress TNBC tumor growth as well as distant metastasis. Gene expression and protein analyses confirm the decreased levels of EMT factors and FOXM1-regulated target genes in tumors and metastatic lesions in the inhibitor-treated animals. The findings suggest that these FOXM1 suppressive compounds may have therapeutic potential in treating triple negative breast cancer, with the aim of reducing tumor progression and metastatic outgrowth.

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Section: Introductionmentioning

confidence: 99%

Suppression of Tumor Growth, Metastasis, and Signaling Pathways by Reducing FOXM1 Activity in Triple Negative Breast Cancer

Dey

Wang

Ziegler

et al. 2020

Cancers

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“…Forkhead box M1 (FOXM1), a member of the Forkhead box transcription factor family, is an oncogenic transcription factor, and its overexpression is associated with poor prognosis in several types of human cancers, such as pancreatic cancer, breast cancer, and lung cancer [ 5 , 6 , 7 ]. FOXM1 is involved in cell cycle progression through regulation of gene expression in the G1/S and G2/M phases and by inducing the proper execution of the mitotic program [ 8 , 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Rosmarinic Acid Methyl Ester Regulates Ovarian Cancer Cell Migration and Reverses Cisplatin Resistance by Inhibiting the Expression of Forkhead Box M1

et al. 2020

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Rosmarinic acid methyl ester (RAME), a derivative of rosmarinic acid (RA), is reported to have several therapeutic effects, including anti-tumor effects against cervical cancer. However, its anti-tumor effects in ovarian cancer is unclear. In this study, we studied the molecular pathways associated with the anti-tumor effects of RAME in ovarian cancer. To identify the effects of RAME in ovarian cancer, RNA sequencing was performed in RAME-treated ovarian cancer cells; we found that RAME treatment downregulated the genes closely involved with the target genes of the transcription factor Forkhead box M1 (FOXM1). It was reported that FOXM1 is overexpressed in a variety of cancer cells and is associated with cell proliferation and tumorigenesis. Therefore, we hypothesized that FOXM1 is a key target of RAME; this could result in its anti-tumor effects. Treatment of ovarian cancer cells with RAME-inhibited cell migration and invasion, as shown by wound healing and transwell migration assays. To examine whether RAME represses the action of FOXM1, we performed quantitative RT-PCR and ChIP-qPCR. Treatment of ovarian cancer cells with RAME decreased the mRNA expression of FOXM1 target genes and the binding of FOXM1 to its target genes. Moreover, FOXM1 expression was increased in cisplatin-resistant ovarian cancer cells, and combination treatment with RAME and cisplatin sensitized the cisplatin-resistant ovarian cancer cells, which was likely due to FOXM1 inhibition. Our research suggests that RAME is a promising option in treating ovarian cancer patients, as it revealed a novel molecular pathway underlying its anti-tumor effects.

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“…Notably, we observed a clear inhibitory effect of Api on FOXM1 and FOXM1 activity. Since FOXM1 is upregulated and overexpressed in aggressive therapy-resistant forms of breast cancer and is associated with worse prognosis of patients [ 43 , 47 ], Api warrants further study as a potential treatment for endocrine-resistant BC.…”

Section: Discussionmentioning

confidence: 99%

Apigenin, a Partial Antagonist of the Estrogen Receptor (ER), Inhibits ER-Positive Breast Cancer Cell Proliferation through Akt/FOXM1 Signaling

Pham

Page

Percevault

et al. 2021

IJMS

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Approximately 80% of breast cancer (BC) cases express the estrogen receptor (ER), and 30–40% of these cases acquire resistance to endocrine therapies over time. Hyperactivation of Akt is one of the mechanisms by which endocrine resistance is acquired. Apigenin (Api), a flavone found in several plant foods, has shown beneficial effects in cancer and chronic diseases. Here, we studied the therapeutic potential of Api in the treatment of ER-positive, endocrine therapy-resistant BC. To achieve this objective, we stably overexpressed the constitutively active form of the Akt protein in MCF-7 cells (named the MCF-7/Akt clone). The proliferation of MCF-7/Akt cells is partially independent of estradiol (E2) and exhibits an incomplete response to the anti-estrogen agent 4-hydroxytamoxifen, demonstrating the resistance of these cells to hormone therapy. Api exerts an antiproliferative effect on the MCF-7/Akt clone. Api inhibits the proliferative effect of E2 by inducing G2/M phase cell cycle arrest and apoptosis. Importantly, Api inhibits the Akt/FOXM1 signaling pathway by decreasing the expression of FOXM1, a key transcription factor involved in the cell cycle. Api also alters the expression of genes regulated by FOXM1, including cell cycle-related genes, particularly in the MCF-7/Akt clone. Together, our results strengthen the therapeutic potential of Api for the treatment of endocrine-resistant BC.

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Suppression of FOXM1 activities and breast cancer growth in vitro and in vivo by a new class of compounds

Cited by 64 publications

References 51 publications

Suppression of Tumor Growth, Metastasis, and Signaling Pathways by Reducing FOXM1 Activity in Triple Negative Breast Cancer

Suppression of Tumor Growth, Metastasis, and Signaling Pathways by Reducing FOXM1 Activity in Triple Negative Breast Cancer

Rosmarinic Acid Methyl Ester Regulates Ovarian Cancer Cell Migration and Reverses Cisplatin Resistance by Inhibiting the Expression of Forkhead Box M1

Apigenin, a Partial Antagonist of the Estrogen Receptor (ER), Inhibits ER-Positive Breast Cancer Cell Proliferation through Akt/FOXM1 Signaling

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