Interactions with Fibroblasts Are Distinct in Basal-Like and Luminal Breast Cancers

Camp, J. Terese; Elloumi, Fathi; Roman-Perez, Erick; Rein, Jessica; Stewart, Delisha A.; Harrell, J. Chuck; Perou, Charles M.; Troester, Melissa A.

doi:10.1158/1541-7786.mcr-10-0372

Cited by 93 publications

(124 citation statements)

References 53 publications

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“…miR-520/373 family directly targets TGFBR2 and their expression inversely correlates in ER À primary breast cancer samples As the pro-inflammatory cytokines IL-6 and IL-8 had previously been reported to modulate cell motility in breast cancer (Wu et al, 2008;Walter et al, 2009;Camp et al, 2011), and NF-kB inhibition in ER À breast cancer cells had been previously reported to abrogate metastasis formation (Park et al, 2007), we hypothesized that miR-373 and miR-520c might have an inhibitory role in cell invasion through deregulation of NF-kB signaling. To investigate this hypothesis, we used the highly invasive and ER À breast carcinoma cell line MDA-MB-231.…”

Section: Resultsmentioning

confidence: 99%

MicroRNA-520/373 family functions as a tumor suppressor in estrogen receptor negative breast cancer by targeting NF-κB and TGF-β signaling pathways

et al. 2011

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MicroRNAs (miRNAs) as modulators of gene expression have been described to display both tumor-promoting and tumor-suppressive functions. Although their role has been studied in different tumor types, little is known about how they regulate nuclear factor jB (NF-jB) signaling in breast cancer. Here, we performed an unbiased whole genome miRNA (miRome) screen to identify novel modulators of NF-jB pathway in breast cancer. The screen identified 13 miRNA families whose members induced consistent effects on NF-jB activity. Among those, the miR-520/373 family inhibited NF-jB signaling through direct targeting of RELA and thus strongly reduced expression and secretion of the pro-inflammatory cytokines interleukin (IL)-6 and IL-8. With a combination of in vitro and in vivo approaches, we propose a metastasis-suppressive role of miR-520/373 family. miR520c and miR-373 abrogated both in vitro cell invasion and in vivo intravasation of highly invasive MDA-MB-231 cells. However, knockdown of RELA did not affect their metastatic ability. mRNA profiling of MDA-MB-231 cells on overexpression of miR-520/373 members revealed a strong downregulation of transforming growth factor-b (TGF-b) signaling. Mechanistically, the metastasis-suppressive role of miR-520/373 can be attributed to direct suppression of TGFBR2, as the silencing of TGFBR2 phenocopied the effects of miR-520/373 overexpression on suppression of Smad-dependent expression of the metastasis-promoting genes parathyroid hormone-related protein, plasminogen activator inhibitor-1 and angiopoietin-like 4 as well as tumor cell invasion, in vitro and in vivo. A negative correlation between miR-520c and TGFBR2 expression was observed in estrogen receptor negative (ER À ) breast cancer patients but not in the ER positive (ER þ ) subtype. Remarkably, decreased expression of miR-520c correlated with lymph node metastasis specifically in ER À tumors. Taken together, our findings reveal that miR-520/373 family has a tumor-suppressive role in ER À breast cancer by acting as a link between the NF-jB and TGF-b pathways and may thus contribute to the interplay of tumor progression, metastasis and inflammation.

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Section: Resultsmentioning

confidence: 99%

MicroRNA-520/373 family functions as a tumor suppressor in estrogen receptor negative breast cancer by targeting NF-κB and TGF-β signaling pathways

et al. 2011

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“…The reduction mammoplasty fibroblast (RMF-GFP) is a stable cell line that constitutively expresses GFP (62). RMF-GFPs were maintained as previously published (28) in RPMI medium. GFP expression was obtained through a lentiviral infection with puromycin as the selection antibiotic.…”

Section: Methodsmentioning

confidence: 99%

“…We then perform GNR diffusion imaging in two biological models where pathology is strongly linked to mechanical properties. The first is an in vitro ECM model of the human mammary stroma, in which the mechanical microenvironment may modulate breast cancer aggressiveness (28,29). The second is that of actively transporting pulmonary mucus, in which the viscoelastic properties of the mucus are modified in diseases such as chronic obstructive pulmonary disease and cystic fibrosis, leading to loss of mucociliary transport and chronic infection (30,31).…”

mentioning

confidence: 99%

Probing biological nanotopology via diffusion of weakly constrained plasmonic nanorods with optical coherence tomography

Chhetri

Blackmon

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Biological materials exhibit complex nanotopology, i.e., a composite liquid and solid phase structure that is heterogeneous on the nanoscale. The diffusion of nanoparticles in nanotopological environments can elucidate biophysical changes associated with pathogenesis and disease progression. However, there is a lack of methods that characterize nanoprobe diffusion and translate easily to in vivo studies. Here, we demonstrate a method based on optical coherence tomography (OCT) to depth-resolve diffusion of plasmon-resonant gold nanorods (GNRs) that are weakly constrained by the biological tissue. By using GNRs that are on the size scale of the polymeric mesh, their Brownian motion is minimally hindered by intermittent collisions with local macromolecules. OCT depth-resolves the particleaveraged translational diffusion coefficient (D T ) of GNRs within each coherence volume, which is separable from the nonequilibrium motile activities of cells based on the unique polarized light-scattering properties of GNRs. We show how this enables minimally invasive imaging and monitoring of nanotopological changes in a variety of biological models, including extracellular matrix (ECM) remodeling as relevant to carcinogenesis, and dehydration of pulmonary mucus as relevant to cystic fibrosis. In 3D ECM models, D T of GNRs decreases with both increasing collagen concentration and cell density. Similarly, D T of GNRs is sensitive to human bronchial-epithelial mucus concentration over a physiologically relevant range. This novel method comprises a broad-based platform for studying heterogeneous nanotopology, as distinct from bulk viscoelasticity, in biological milieu.dynamic light scattering | plasmon resonance | nanoparticle diffusion | diffusion in mucus | diffusion in extracellular matrix B iological fluids (e.g., blood, mucus, saliva, synovial fluids) and soft solids [e.g., collagen, extracellular matrix (ECM), cytoskeleton] consist of a milieu of small molecules (making up the solvent) and large molecules (proteins and polymers making up the mesh or matrix) that are collectively responsible for their viscoelastic nature. Traditional rheological methods characterize the bulk viscoelastic properties of such biological media. However, nanoscopic objects, such as viruses and drugs that are smaller than the polymeric correlation length of the biological tissue network, encounter mechanical environments that are entirely different from that described by bulk viscoelasticity. For instance, at the nanoscale, mucus is a heterogeneous network of mucin fibers, nonmucin proteins, cell debris, lipids, DNA, actin filaments, and salts in a low-viscosity interstitial fluid (1). Similarly, tissue ECM, although soft solid-like in bulk, is an interconnected mesh of elongated protein fibers riddled with pores that are filled with low-viscosity interstitial fluids.Microrheological techniques based on the generalized StokesEinstein relation (2-5) are capable of converting the observed diffusion of probes of controlled hydrodynamic size into a mea...

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“…Fresh tissues from invasive tumors, non-neoplastic adjacent breast tissue and mammary fat tissue were collected at the time of breast surgery and snap frozen in liquid nitrogen. Based on in vitro evidence that basal-like and luminal tumors are associated with distinctive microenvironments (20), we oversampled these subtypes. All of the participants provided written informed consent under a protocol approved by the U.S. National Cancer Institute and local (Polish) institutional review boards.…”

Section: Methodsmentioning

confidence: 99%

Benign Breast Tissue Composition in Breast Cancer Patients: Association with Risk Factors, Clinical Variables, and Gene Expression

Sun¹,

Sandhu

Figueroa

et al. 2014

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Introduction Breast tissue composition (epithelium, non-fatty stroma, and adipose) changes qualitatively and quantitatively throughout the lifespan, and may mediate relationships between risk factors and breast cancer initiation. We sought to identify relationships between tissue composition, risk factors, tumor characteristics, and gene expression. Methods Participants were 146 patients from the Polish Breast Cancer Study, with data on risk factor and clinicopathological characteristics. Benign breast tissue composition was evaluated using digital image analysis of histological sections. Whole genome microarrays were performed on the same tissue blocks. Results Mean epithelial, non-fatty stromal, and adipose proportions were 8.4% (SD=4.9%), 27.7% (SD=24.0%), and 64.0% (SD=24.0%), respectively. Among women < 50 years old, stroma proportion decreased and adipose proportion increased with age, with approximately 2% difference per year (p <0.01). The variation in epithelial proportion with age was modest (0.1% per year). Higher epithelial proportion was associated with obesity (7.6% in non-obese vs 10.1% in obese; p=0.02) and with poorly differentiated tumors (7.8% in well/moderate vs 9.9% in poor; p=0.05). Gene expression signatures associated with epithelial and stromal proportion were identified and validated. Stroma-associated genes were in metabolism and stem cell maintenance pathways, while epithelial genes were enriched for cytokine and immune response pathways. Conclusions Breast tissue composition was associated with age, BMI, and tumor grade, with consequences for breast gene expression. Impact Breast tissue morphologic factors may influence breast cancer etiology. Composition and gene expression may act as biomarkers of breast cancer risk and progression.

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Interactions with Fibroblasts Are Distinct in Basal-Like and Luminal Breast Cancers

Cited by 93 publications

References 53 publications

MicroRNA-520/373 family functions as a tumor suppressor in estrogen receptor negative breast cancer by targeting NF-κB and TGF-β signaling pathways

MicroRNA-520/373 family functions as a tumor suppressor in estrogen receptor negative breast cancer by targeting NF-κB and TGF-β signaling pathways

Probing biological nanotopology via diffusion of weakly constrained plasmonic nanorods with optical coherence tomography

Benign Breast Tissue Composition in Breast Cancer Patients: Association with Risk Factors, Clinical Variables, and Gene Expression

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