Epigenetic regulation of bone morphogenetic protein-6 gene expression in breast cancer cells

Zhang, Ming; Wang, Qing; Yuan, Wei; Yang, Shuang; Wang, Xu; Yan, Ji; Du, Jie; Yin, Jian; Gao, Song; Sun, Bei; Zhu, Ting

doi:10.1016/j.jsbmb.2007.01.002

Cited by 36 publications

(38 citation statements)

References 18 publications

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“…BMP6 expression in ER-negative breast cancer was obviously lower than that in ER-positive breast cancer. Previous studies have shown that promoter hypermethylation contributes to the downregulation of BMP6 expression in ER-negative breast cancer patients (15,16). Our results were in agreement with a previous observation (7) and moreover, further analysis also revealed a significant association between tumor cell grade and BMP6 expression in tumor tissues.…”

Section: Discussionsupporting

confidence: 93%

Downregulation of BMP6 enhances cell proliferation and chemoresistance via activation of the ERK signaling pathway in breast cancer

Lian

Liu

et al. 2013

Oncology Reports

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Abstract. Previous studies indicate that bone morphogenetic protein (BMP) 6 is involved in breast cancer development and progression. However, the mechanism underlying the role of BMP6 in breast cancer cell proliferation, differentiation and chemoresistance remains unknown. In this study, we confirmed that BMP6 expression was downregulated in breast cancer tissues compared with the adjacent normal breast tissues. We further demonstrated that the downregulation of BMP6 was correlated with the estrogen receptor (ER) and progesterone receptor (PR) status, tumor grade and enhanced proliferation (Ki67 proliferation index). In vitro functional experiments showed that the suppression of BMP6 expression by a specific small hairpin (sh)RNA vector led to increased proliferation in the MCF7 breast cancer cell line. Furthermore, knockdown of BMP6 in MCF7 cells enhanced the chemoresistance to doxorubicin by upregulation of mdr-1/P-gp expression and activation of the ERK signaling pathway. Taken together, our data suggest that BMP6 plays a critical role in breast cancer cell aberrant proliferation and chemoresistance and may serve as a novel diagnostic biomarker or therapeutic target for breast cancer.

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Section: Discussionsupporting

confidence: 93%

Downregulation of BMP6 enhances cell proliferation and chemoresistance via activation of the ERK signaling pathway in breast cancer

Lian

Liu

et al. 2013

Oncology Reports

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“…These observations indicate that the ER pathway is closely associated with the BMP pathway during bone development and remodeling. In previous studies, BMP-6 expression was determined to be activated by estrogen in the MCF-7 breast cancer cell line (29). It was also reported that BMP-2-induced the activation of Smad activity and that BMP-2-mediated gene expression was suppressed by E2 in breast cancer cells via direct physical interactions between Smads and ER (30).…”

Section: Discussionmentioning

confidence: 94%

Induction of estrogen receptor α-36 expression by bone morphogenetic protein 2 in breast cancer cell lines

Wang

Huang

Baowei

et al. 2012

Molecular Medicine Reports

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Abstract. The expression of estrogen receptor-α (ERα) is one of the most important diagnostic and prognostic factors of breast cancer. Recently, ERα-36 has been identified as a novel variant of ER-α. ERα-36 lacks intrinsic transcription activity and mainly mediates non-genomic estrogen signaling. Bone morphogenetic proteins (BMPs) are recognized as key factors during the control of cell fate and cancer development. However, the correlation between BMP and the ER signaling pathway remains unclear. In this study, we show that BMP2, a member of the BMP family, is a novel inducer of ERα-36 expression in breast cancer cells. As shown by western blot assays, the upregulation of ERα-36 by BMP2 was significant. In MDA-MB-231 cells which are ERα-66-negative, BMP2 was able to induce the expression of ERα-36 in a dose-dependent manner, and the RNA interference assay indicated a correlation between BMP2 and ERα-36 expression. BMP2 inhibited the growth of MCF-7 and MDA-MB-231 cells; however, the inhibitory effect was antagonized by tamoxifen, suggesting that the ER signal was involved. The growth of MDA-MB-231 cells was stimulated by 17-β-estradiol (E2) after BMP2 induction, even though the cells were previously insensitive to E2. These results suggest that BMP2 induces ERα-36 expression and alters tumor resistance to endocrine therapy by changing the expression profile of ERs.

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“…BMP family proteins are members of the transforming growth factor-β (TGF-β) superfamily and critical mediators of early embryonic patterning involved in skeletal development and bone formation (7,8). Inactivation of the BMP genes has been reported in several cancer types, including lung, breast, prostate and colon cancers, lymphomas and mesotheliomas (9)(10)(11)(12)(13)(14)(15), suggesting the importance of BMPs in tumorigenesis of these cancers. As an antagonist of BMP proteins, Gremlin also plays important roles during early development (16)(17)(18)(19), as well as tumorigenesis of several types of cancers (20)(21)(22)(23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%

The bone morphogenetic protein antagonist Gremlin is overexpressed in human malignant mesothelioma

et al. 2011

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Abstract.Gremlin is a member of the bone morphogenetic protein (BMP) antagonist family and its antagonistic effect is likely through direct binding to BMP proteins. As an antagonist of BMP, Gremlin plays a role in regulating organogenesis, body patterning and tissue differentiation. Recent studies have shown a deregulation of Gremlin in several types of human cancers. However, the role of Gremlin in human malignant mesothelioma (MM) is still unknown. In this study, we investigated the expression of Gremlin in human MM. We found that Gremlin mRNA and protein were both overexpressed in the majority of primary MM tissue samples that we examined. We also observed high level expression of the Gremlin gene in 4 of the 6 MM cell lines. Consistently, we found that the Gremlin promoter activity was significantly elevated in those MM cell lines expressing the Gremlin gene. On the other hand, no activity of the Gremlin promoter was detected in the two MM cell lines lacking Gremlin expression. Moreover, to examine the functional significance of the Gremlin overexpression in MM, we used shRNA to knock down Gremlin expression in MM cell lines expressing Gremlin and found that inhibition of Gremlin expression significantly suppressed proliferation of those MM cells. Taken together, our results suggest that the BMP antagonist Gremlin is overexpressed in MM and that aberrant activation of Gremlin may play a critical role in the tumorigenesis of human MM.

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Epigenetic regulation of bone morphogenetic protein-6 gene expression in breast cancer cells

Cited by 36 publications

References 18 publications

Downregulation of BMP6 enhances cell proliferation and chemoresistance via activation of the ERK signaling pathway in breast cancer

Downregulation of BMP6 enhances cell proliferation and chemoresistance via activation of the ERK signaling pathway in breast cancer

Induction of estrogen receptor α-36 expression by bone morphogenetic protein 2 in breast cancer cell lines

The bone morphogenetic protein antagonist Gremlin is overexpressed in human malignant mesothelioma

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