Endometrial Cancer-Associated FGF18 Expression Is Reduced by Bazedoxifene in Human Endometrial Stromal Cells In Vitro and in Murine Endometrium

Flannery, Clare; Fleming, Andrew G; Choe, Gina; Naqvi, Hanyia; Zhang, Margaret; Sharma, Anu; Taylor, Hugh S.

doi:10.1210/en.2016-1233

Cited by 13 publications

(19 citation statements)

References 43 publications

(48 reference statements)

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“…Accounting for the pharmacokinetic difference between humans and mice, the FDA‐recommended daily intake of 20 mg bazedoxifene for a 60 kg woman corresponds to a dose of approximately 4.1 mg/kg/day in mice (Nair & Jacob, ). The latter dose is consistent with the 3 mg/kg dose administered here and in some of the previous studies documenting the anti‐estrogen activities of bazedoxifene in mice (Sakr et al , ; Flannery et al , ). Thus, the safety profile of bazedoxifene may confer benefits to a large (aging) population.…”

Section: Discussionsupporting

confidence: 91%

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Repurposing the selective estrogen receptor modulator bazedoxifene to suppress gastrointestinal cancer growth

et al. 2019

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Excessive signaling through gp130, the shared receptor for the interleukin ( IL )6 family of cytokines, is a common hallmark in solid malignancies and promotes their progression. Here, we established the in vivo utility of bazedoxifene, a steroid analog clinically approved for the treatment of osteoporosis, to suppress gp130‐dependent tumor growth of the gastrointestinal epithelium. Bazedoxifene administration reduced gastric tumor burden in gp130 Y757F mice, where tumors arise exclusively through excessive gp130/ STAT 3 signaling in response to the IL 6 family cytokine IL 11. Likewise, in mouse models of sporadic colon and intestinal cancers, which arise from oncogenic mutations in the tumor suppressor gene Apc and the associated β‐catenin/canonical WNT pathway, bazedoxifene treatment reduces tumor burden. Consistent with the proposed orthogonal tumor‐promoting activity of IL 11‐dependent gp130/ STAT 3 signaling, tumors of bazedoxifene ‐treated Apc ‐mutant mice retain excessive nuclear accumulation of β‐catenin and aberrant WNT pathway activation. Likewise, bazedoxifene treatment of human colon cancer cells harboring mutant APC did not reduce aberrant canonical WNT signaling, but suppressed IL 11‐dependent STAT 3 signaling. Our findings provide compelling proof of concept to support the repurposing of bazedoxifene for the treatment of gastrointestinal cancers in which IL 11 plays a tumor‐promoting role.

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Section: Discussionsupporting

confidence: 91%

“…five times per week (Fig A). This dosing was previously used to document inhibitory effects on estrogen‐sensitive mouse tissue (Sakr et al , ; Flannery et al , ). We consistently detected significantly smaller and fewer tumors in the bazedoxifene ‐treated cohorts compared with the vehicle‐treated cohorts (Figs B–D and EV1A).…”

Section: Resultsmentioning

confidence: 99%

Repurposing the selective estrogen receptor modulator bazedoxifene to suppress gastrointestinal cancer growth

et al. 2019

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“…Increased FGF18 expression, which plays a key role in controlling tumor growth and invasion, was associated with tumor progression and poor overall survival in patients (13)(14)(15). FGF18 can also affect both the tumor and the connective tissue cells of the tumor microenvironment (16,17). Overexpression of FGF18 promoted tumor progression by modulating migration, invasion and tumorigenicity of cancer cells arguably through different signaling pathways (13,15).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the growth of hepatocellular carcinoma cells through fibroblast growth factor 18 suppressed by miR-139

et al. 2017

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Abstract. Hepatocellular carcinoma (HCC) is a highly malignant tumor and one of the most common causes for human cancer-related deaths. Fibroblast growth factor 18 (FGF18) is overexpressed in many types of cancer, and is associated with cell proliferation, invasion and angiogenesis. miR-139 has recently been reported as a tumor suppressor in various types of cancer and it can regulate many tumor-related genes, however its association with FGF18 expression in HCC has not been reported and thus remains unknown. In the present study, to explore the potential regulation mechanism of miR-139 with FGF18 in HCC, HCC tissues and cell lines were used. The results revealed that FGF18 was highly expressed in HCC tissues and cells, however miR-139 was lowly expressed. FGF18 was demonstrated to be a direct target of miR-139. Furthermore, the suppressive effect of miR-139 on FGF18 and in turn on proliferation, apoptosis, invasion, migration and tumor-induced angiogenesis of HCC cells was investigated. FGF18 was suggested as a prognostic biomarker and therapeutic target in HCC patients and miR-139 may be a promising strategy used in HCC treatment via the suppression of FGF18.

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“…HAND2 protein expression location, using ab60037 and ab200040, was in the cytosol of the cells. Previous reports, using an antibody that has been discontinued (sc-9409, Santa Cruz Biotechnology), revealed that HAND2 expression was mainly nuclear [8,22]. This discrepancy could be related to the differences between the antibodies.…”

Section: Discussionmentioning

confidence: 99%

Heart and Neural Crest Derivatives Expressed Transcript 2 (HAND2) is Reduced in Women with Breast Cancer. A Case-Control Study

Neto¹,

Pedrini²,

Gross³

et al. 2019

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Background: The search for new markers for breast cancer (BC) has been sought in order to better understand this type of cancer. The Heart and Neural Crest Derivatives Expressed Transcript 2 (HAND2) has been related to endometrial cancer but there are scant data related to BC. The aim of this study is to compare the immunohistochemical expression of HßAND2 in normal breast tissue vs. BC and to correlate with the estrogen receptor (ERα). Patients and Methods: In this case-control study, 19 formalin–fixed, paraffin-embedded tissues were obtained from pathological archives. Benign (n=9; control) and cancer (n=10) breast tissue were analyzed with immunohistochemistry for HAND2 (Ab60037), at dilution 1:50 at pH 9 and ERα (SP1). ImageJ software with "color deconvolution" was used for analysis of the expression of these proteins. The sample size was calculated (power=95%, α error= 1%) to identify an increase from mean 15 DAB units (control) to 40 DAB units in cancer. Results: HAND2 expression (mean ± SD) was 15.5 ± 6.1 (cancer) versus 44.8 ± 21.1 (control) (P=0.002, Student t-test). Its expression was mainly present in the cytosol of the cells. No correlation was observed between ERα and HAND2 (Pearson r = -0.28 (95%CI=-0.6 to 0.22; P=0.2). Conclusions: The protein expression of HAND2, using Ab60037 antibody, is reduced in breast cancer, compared with normal breast tissue. The expression of HAND2 is not correlated with ERα expression.

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Endometrial Cancer-Associated FGF18 Expression Is Reduced by Bazedoxifene in Human Endometrial Stromal Cells In Vitro and in Murine Endometrium

Cited by 13 publications

References 43 publications

Repurposing the selective estrogen receptor modulator bazedoxifene to suppress gastrointestinal cancer growth

Repurposing the selective estrogen receptor modulator bazedoxifene to suppress gastrointestinal cancer growth

Inhibition of the growth of hepatocellular carcinoma cells through fibroblast growth factor 18 suppressed by miR-139

Heart and Neural Crest Derivatives Expressed Transcript 2 (HAND2) is Reduced in Women with Breast Cancer. A Case-Control Study

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