BMP7 inhibits branching morphogenesis in the prostate gland and interferes with Notch signaling

Grishina, Irina; Kim, Sung Yup; Ferrara, Christopher; Makarenkova, Helen P.; Walden, Paul D.

doi:10.1016/j.ydbio.2005.08.018

Cited by 94 publications

(147 citation statements)

References 61 publications

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“…The observed increased potency of BMP2/7 (compared with BMP2 or BMP7 alone) may, therefore, at least in part be caused by the increase in bioavailability due to the diminished efficacy of locally produced Noggin. Of note, BMP7 inhibits epithelial proliferation, branching morphogenesis and ductal budding in the normal development of the prostate, and is also associated with decreased Notch signaling (Grishina et al, 2005), a critical pathway during morphogenesis of epithelial tissues. In this context, the BMP antagonist Noggin can have a key regulatory role in BMP4 and BMP7 action in tissue epithelial stem cells (Cook et al, 2007).…”

Section: Bmp2/7 Inhibits the Breast Cancer Stem Cell Subpopulation Jtmentioning

confidence: 99%

The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation

et al. 2011

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Accumulating evidence suggests that a subpopulation of breast cancer cells, referred to as cancer stem cells (CSCs), have the ability to propagate a tumor and potentially seed new metastases. Furthermore, stimulation of an epithelialto-mesenchymal transition by factors like transforming growth factor-b (TGFb) is accompanied with the generation of breast CSCs. Previous observations indicated that bone morphogenetic protein-7 (BMP7) antagonizes the protumorigenic and prometastatic actions of TGFb, but whether BMP7 action is mechanistically linked to breast CSCs has remained elusive. Here, we have studied the effects of BMP7, BMP2 and a BMP2/7 heterodimer on the formation of human breast CSCs (ALDH hi /CD44 hi / CD24 À/low ) and bone metastases formation in a preclinical model of intra-cardiac injection of MDA-MB-231 cells in athymic nude (Balb/c nu/nu) mice. The BMP2/7 heterodimer was the most efficient stimulator of BMP signaling and very effectively reduced TGFb-driven Smad signaling and cancer cell invasiveness. The tested BMPs-particularly the heterodimeric BMP2/7-strongly reduced the size of the ALDH hi /CD44 hi /CD24 À/low CSC subpopulation. In keeping with these in vitro observations, pretreatment of cancer cells with BMPs for 72 h prior to systemic inoculation of the cancer cells inhibited the formation of bone metastases. Collectively, our data support the notion that breast CSCs are involved in bone metastasis formation and describe heterodimeric BMP2/7 as a powerful TGFb antagonist with anti-metastatic potency.

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Section: Bmp2/7 Inhibits the Breast Cancer Stem Cell Subpopulation Jtmentioning

confidence: 99%

The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation

et al. 2011

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“…Epidermal growth factor (Saito and Mizuno, 1997), homeobox genes (Podlasek et al, 1997;Warot et al, 1997), and both low-dose and high-dose estrogens (vom Saal et al, 1997) have been shown to influence budding, but the mechanisms by which these effects occur is unclear. The bone morphogenetic proteins (BMPs) 4 and 7 (Cook et al, 2007;Grishina et al, 2005) and wingless integration site A (WNT5A; unpublished observations) can directly inhibit bud formation while hedgehog (Hh) signaling has been implicated as a positive regulator of budding (Podlasek et al, 1999;Lamm et al, 2002;Doles et al, 2006). What remains to be determined is how these positive and negative influences are orchestrated to yield the reproducible pattern and quantity of buds that form on select surfaces of the male mouse UGS during fetal development.…”

Section: Introductionmentioning

confidence: 99%

Retinoic acid induces prostatic bud formation

Vezina

Allgeier

Fritz

et al. 2008

Developmental Dynamics

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Formation of prostatic buds from the urogenital sinus (UGS) to initiate prostate development requires localized action of several morphogenetic factors. This report reveals all-trans-retinoic acid (RA) to be a powerful inducer of mouse prostatic budding that is associated with reciprocal changes in expression of two regulators of budding: sonic hedgehog (Shh) and bone morphogenetic protein 4 (Bmp4). Localization of retinoid signaling and expression of RA synthesis, metabolism, and receptor genes in the UGS on embryonic days 14.5-17.5 implicate RA in the mechanism of bud initiation. In UGS organ culture, RA increased prostatic budding, increased Shh expression, and decreased Bmp4. Prostatic budding was stimulated in the absence of RA by recombinant SHH, by blocking BMP4 signaling with NOGGIN, or by combined treatment with SHH and NOGGIN in UGS organ culture media. These observations suggest that reciprocal changes in hedgehog and BMP signaling by RA may regulate bud initiation. Developmental Dynamics 237:1321-1333, 2008.

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“…There are no significant changes in the expression of Shh, FGF7, FGF10 or BMP7, known to inhibit branching morphogenesis in the prostate. 42 In the pes-ERaKO, expression levels of these genes showed no significant difference. We also observed that expression of IGF-1 decreases and BMP4 increases in the DLP of FSP-ERaKO (Figure 6b).…”

Section: Prostate Branching Morphogenesis In Fsp-mentioning

confidence: 94%

Reduced prostate branching morphogenesis in stromal fibroblast, but not in epithelial, estrogen receptor α knockout mice

Chen¹,

Yeh²,

Shyr³

et al. 2012

Asian J Androl

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Early studies suggested that estrogen receptor alpha (ERa) is involved in estrogen-mediated imprinting effects in prostate development. We recently reported a more complete ERa knockout (KO) mouse model via mating b-actin Cre transgenic mice with floxed ERa mice. These ACTB-ERaKO male mice showed defects in prostatic branching morphogenesis, which demonstrates that ERa is necessary to maintain proliferative events in the prostate. However, within which prostate cell type ERa exerts those important functions remains to be elucidated. To address this, we have bred floxed ERa mice with either fibroblast-specific protein (FSP)-Cre or probasin-Cre transgenic mice to generate a mouse model that has deleted ERa gene in either stromal fibroblast (FSP-ERaKO) or epithelial (pes-ERaKO) prostate cells. We found that circulating testosterone and fertility were not altered in FSP-ERaKO and pes-ERaKO male mice. Prostates of FSP-ERaKO mice have less branching morphogenesis compared to that of wild-type littermates. Further analyses indicated that loss of stromal ERa leads to increased stromal apoptosis, reduced expression of insulin-like growth factor-1 (IGF-1) and FGF10, and increased expression of BMP4. Collectively, we have established the first in vivo prostate stromal and epithelial selective ERaKO mouse models and the results from these mice indicated that stromal fibroblast ERa plays important roles in prostatic branching morphogenesis via a paracrine fashion. Selective deletion of the ERa gene in mouse prostate epithelial cells by probasin-Cre does not affect the regular prostate development and homeostasis.

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BMP7 inhibits branching morphogenesis in the prostate gland and interferes with Notch signaling

Cited by 94 publications

References 61 publications

The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation

The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation

Retinoic acid induces prostatic bud formation

Reduced prostate branching morphogenesis in stromal fibroblast, but not in epithelial, estrogen receptor α knockout mice

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