Ubiquitous Brms1 expression is critical for mammary carcinoma metastasis suppression via promotion of apoptosis

Cook, Leah M.; Cao, Xuemei; Dowell, Alexander E.; Debies, Michael T.; Edmonds, Mick D.; Beck, Benjamin H.; Kesterson, Robert A.; Desmond, Reneé A.; Frost, Andra R.; Hurst, Douglas R.; Welch, Danny R.

doi:10.1007/s10585-012-9452-x

Cited by 13 publications

(9 citation statements)

References 43 publications

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“…More comprehensive analyses of complexes will be required in order to fully interpret these data. Corroborating these notions, we recently reported that BRMS1 expression alone was not sufficient to suppress metastasis using mouse models of metastatic mammary carcinoma [43].…”

Section: Discussionmentioning

confidence: 97%

The C-Terminal Putative Nuclear Localization Sequence of BReast cancer Metastasis Suppressor 1, BRMS1, Is Necessary for Metastasis Suppression

et al. 2013

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Breast cancer metastasis suppressor 1 (BRMS1) is a predominantly nuclear protein that suppresses metastasis in multiple human and murine carcinoma cell lines. BRMS1 interacts with several nuclear proteins including SIN3:HDAC chromatin remodeling complexes that are involved in repressing transcription. However, recent reports suggest BRMS1 may function in the cytoplasm. BRMS1 has two predicted nuclear localization sequences (NLS) that are located near the C-terminus (amino acids 198–205 and 238–244, NLS1 and NLS2 respectively). We hypothesized that nuclear localization sequences of BRMS1 were essential for BRMS1 mediated metastasis suppression. Replacement of NLS2 with NLS1 (BRMS1NLS1,1), truncation at 238 (BRMS1ΔNLS2), or switching the location of NLS1 and NLS2 (BRMS1NLS2,1) did not affect nuclear localization; but, replacement of NLS1 with NLS2 (BRMS1NLS2,2) or truncation at 197 (BRMS1ΔNLS which removes both NLS) promoted cytoplasmic localization. MDA-MB-231 human metastatic breast cancer cells transduced with BRMS1NLS1,1, BRMS1NLS2,2 or BRMS1NLS2,1 were evaluated for metastasis suppression in an experimental xenograft mouse model. Interestingly, while NLS2 was not necessary for nuclear localization, it was found to be important for metastasis suppression since BRMS1NLS2,2 suppressed metastasis by 85%. In contrast, BRMS1NLS2,1 and BRMS1NLS1,1 did not significantly suppress metastasis. Both BRMS1 and BRMS1NLS2,2 co-immunoprecipitated with SIN3A in the nucleus and cytoplasm; however, BRMS1NLS1,1 and BRMS1NLS2,1 were associated with SIN3A in the nucleus only. Moreover, BRMS1 and BRMS1NLS2,2, but not BRMS1NLS1,1 and BRMS1NLS2,1, down-regulated the pro-metastatic microRNA, miR-10b. Together, these data demonstrate an important role for NLS2 in the cytoplasm that is critical for metastasis suppression and is distinct from nuclear localization.

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Section: Discussionmentioning

confidence: 97%

The C-Terminal Putative Nuclear Localization Sequence of BReast cancer Metastasis Suppressor 1, BRMS1, Is Necessary for Metastasis Suppression

et al. 2013

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“…Immunohistochemical analyses of osteocalcin was performed as previously described (Cook et al, 2013). Briefly, excised femurs were submerged in 10% neutral buffered formalin (Sigma, St Louis, MO) for fixation before decalcification with 10% EDTA and paraffin embedment.…”

Section: Methodsmentioning

confidence: 99%

Increased trabecular bone and improved biomechanics in an osteocalcin null rat model created by CRISPR/Cas9 technology

Lambert

Challa

Niu

et al. 2016

Disease Models &Amp; Mechanisms

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Osteocalcin, also known as bone γ-carboxyglutamate protein (Bglap), is expressed by osteoblasts and is commonly used as a clinical marker of bone turnover. A mouse model of osteocalcin deficiency has implicated osteocalcin as a mediator of changes to the skeleton, endocrine system, reproductive organs and central nervous system. However, differences between mouse and human osteocalcin at both the genome and protein levels have challenged the validity of extrapolating findings from the osteocalcin-deficient mouse model to human disease. The rat osteocalcin (Bglap) gene locus shares greater synteny with that of humans. To further examine the role of osteocalcin in disease, we created a rat model with complete loss of osteocalcin using the CRISPR/Cas9 system. Rat osteocalcin was modified by injection of CRISPR/Cas9 mRNA into the pronuclei of fertilized single cell Sprague-Dawley embryos, and animals were bred to homozygosity and compound heterozygosity for the mutant alleles. Dual-energy X-ray absorptiometry (DXA), glucose tolerance testing (GTT), insulin tolerance testing (ITT), microcomputed tomography (µCT), and a three-point break biomechanical assay were performed on the excised femurs at 5 months of age. Complete loss of osteocalcin resulted in bones with significantly increased trabecular thickness, density and volume. Cortical bone volume and density were not increased in null animals. The bones had improved functional quality as evidenced by an increase in failure load during the biomechanical stress assay. Differences in glucose homeostasis were observed between groups, but there were no differences in body weight or composition. This rat model of complete loss of osteocalcin provides a platform for further understanding the role of osteocalcin in disease, and it is a novel model of increased bone formation with potential utility in osteoporosis and osteoarthritis research.

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“…At weaning (~3 weeks of age) mice were genotyped for presence of the PyMT transgene as previously described (12, 18). mtDNA haplotypes were also confirmed in all female transgene-positive F 1 progeny by RFLP (restriction fragment length polymorphism) analysis of PCR products screening for diagnostic mtDNA SNPs that differentiate between the FVB, C57BL/6, and BALB/c mtDNA, as previously described (17).…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial Genetics Regulate Breast Cancer Tumorigenicity and Metastatic Potential

et al. 2015

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Current paradigms of carcinogenic risk suggest that genetic, hormonal, and environmental factors influence an individual’s predilection for developing metastatic breast cancer. Investigations of tumor latency and metastasis in mice have illustrated differences between inbred strains, but the possibility that mitochondrial genetic inheritance may contribute to such differences in vivo has not been directly tested. In this study, we tested this hypothesis in mitochondrial-nuclear exchange (MNX) mice we generated, where cohorts shared identical nuclear backgrounds but different mtDNA genomes on the background of the PyMT transgenic mouse model of spontaneous mammary carcinoma. In this setting, we found that primary tumor latency and metastasis segregated with mtDNA, suggesting that mtDNA influences disease progression to a far greater extent than previously appreciated. Our findings prompt further investigation into metabolic differences controlled by mitochondrial process as a basis for understanding tumor development and metastasis in individual subjects.

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Ubiquitous Brms1 expression is critical for mammary carcinoma metastasis suppression via promotion of apoptosis

Cited by 13 publications

References 43 publications

The C-Terminal Putative Nuclear Localization Sequence of BReast cancer Metastasis Suppressor 1, BRMS1, Is Necessary for Metastasis Suppression

The C-Terminal Putative Nuclear Localization Sequence of BReast cancer Metastasis Suppressor 1, BRMS1, Is Necessary for Metastasis Suppression

Increased trabecular bone and improved biomechanics in an osteocalcin null rat model created by CRISPR/Cas9 technology

Mitochondrial Genetics Regulate Breast Cancer Tumorigenicity and Metastatic Potential

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