Characterization of a Stem-like Subpopulation in Basal-like Ductal Carcinoma in Situ (DCIS) Lesions

Li, Qinglin; Eades, Gabriel; Yao, Yuan; Zhang, Yongshu; Zhou, Qun

doi:10.1074/jbc.m113.502278

Cited by 76 publications

(76 citation statements)

References 22 publications

(26 reference statements)

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“…We have shown that miR-140 inhibits expression of stem cell factors SOX2, SOX9, and ALDH1, suppressing breast cancer stem cells and preventing breast cancer initiation and progression. In estrogen receptorpositive breast cancer, miR-140 is downregulated due to estrogen-mediated transcriptional inhibition, whereas in basal-like breast cancers, epigenetic mechanisms of inhibition have been demonstrated (20)(21)(22). We have shown that miR-140 is highly expressed in preadipocytes (23) and is necessary for adipose-derived stem cell adipogenesis under normal physiological conditions (24).…”

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confidence: 83%

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A High-Fat Diet Promotes Mammary Gland Myofibroblast Differentiation through MicroRNA 140 Downregulation

Wolfson

Zhang

Gernapudi

et al. 2017

Molecular and Cellular Biology

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Human breast adipose tissue is a heterogeneous cell population consisting of mature white adipocytes, multipotent mesenchymal stem cells, committed progenitor cells, fibroblasts, endothelial cells, and immune cells. Dependent on external stimulation, adipose-derived stem cells differentiate along diverse lineages into adipocytes, chondrocytes, osteoblasts, fibroblasts, and myofibroblasts. It is currently not fully understood how a high-fat diet reprograms adipose-derived stem cells into myofibroblasts. In our study, we used mouse models of a regular diet and of high-fat-diet-induced obesity to investigate the role of dietary fat on myofibroblast differentiation in the mammary stromal microenvironment. We found that a high-fat diet promotes myofibroblast differentiation by decreasing microRNA 140 (miR-140) expression in mammary adipose tissue through a novel negative-feedback loop. Increased transforming growth factor ␤1 (TGF-␤1) in mammary adipose tissue in obese mice activates SMAD3 signaling, causing phospho-SMAD3 to bind to the miR-140 locus and inhibit miR-140 transcription. This prevents miR-140 from targeting SMAD3 for degradation, resulting in amplified TGF-␤1/SMAD3 signaling and miR-140 downregulation-dependent myofibroblast differentiation. Using tissue and coculture models, we found that myofibroblasts and the fibrotic microenvironment created by myofibroblasts impact the stemness and proliferation of normal ductal epithelial cells and early-stage breast cancer invasion and stemness.KEYWORDS Obesity, breast cancer, fibrosis, miRNA, myofibroblasts T he heterogeneous cell population found within the mammary stromal vascular fraction (SVF) is essential for extracellular matrix (ECM) remodeling and disease development. Despite the importance of the mammary adipose tissue, surprisingly little is known about normal tissue homeostasis. The SVF consists of multipotent mesenchymal stem cells, committed progenitor cells, fibroblasts, endothelial cells, and immune cells. Under the influence of a variety of hormones, growth factors, and external factors, mesenchymal stem cells (MSCs) in the stromal vascular fraction are able to differentiate into a multitude of cell types, including adipocytes, chondrocytes, osteoblasts, fibroblasts, and myofibroblasts. For example, to commit MSCs into the adipogenic lineage in vitro, the master regulators peroxisome proliferator-activated receptor gamma (PPAR␥) and C/EBP␣ are induced using a combination of dexamethasone, indomethacin, insulin, and methylisobutylxanthine, whereas in osteoblast differentiation, RUNX2 is activated using a mixture of ascorbate, bone morphogenetic protein, dexamethasone, and 1,25-dihydroxy vitamin D 3 (1). While these cocktails can be used to induce differentiation, the complex signaling pathways regulating adipose MSCs are not fully elucidated.Fibroblasts are critical for the production and maintenance of the extracellular matrix through secretion of ECM proteins, including fibronectin and collagen as well as

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confidence: 83%

“…The SMAD3 overexpression plasmid pQCXIH-Flag Smad3 WT was a gift from Joan Massague (Addgene plasmid 27025) (36). All transfection assays were performed as described previously by Li et al (20).…”

Section: Methodsmentioning

confidence: 99%

A High-Fat Diet Promotes Mammary Gland Myofibroblast Differentiation through MicroRNA 140 Downregulation

Wolfson

Zhang

Gernapudi

et al. 2017

Molecular and Cellular Biology

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“…The sulforaphane was dissolved in ethyl alcohol (EtOH). All transfection assays were performed as described previously by Li et al (16). For actinomycin D RNA stability, cells were grown to ϳ50% confluence and treated with 10 g/ml actinomycin D (Sigma) in dimethyl sulfoxide (DMSO).…”

Section: Methodsmentioning

confidence: 99%

“…Through targeted degradation of the stem cell factors SRY (sex-determining region Y) box 2 (SOX2), SOX9, and ALDH1, miR-140 prevents breast cancer initiation and progression. Expression of miR-140 is downregulated in estrogen receptor-positive breast cancers due to estrogen-mediated transcriptional inhibition, while epigenetic mechanisms of inhibition have been demonstrated in basal-like breast cancers (16,18). Decreased miR-140 expression releases suppression of breast cancer stem cells, leading to higher tumorigenicity.…”

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confidence: 99%

“…Several miRNAs have been found to play important regulatory roles in either promoting (miR-140, miR-26a/b, and miR-455) (11,12) or suppressing (miR-27 and miR-133) adipogenesis (13,14). miR-140 is an important regulator of developmental pathways and stem cell differentiation and is a tumor suppressor in breast cancer (15)(16)(17). Through targeted degradation of the stem cell factors SRY (sex-determining region Y) box 2 (SOX2), SOX9, and ALDH1, miR-140 prevents breast cancer initiation and progression.…”

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confidence: 99%

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MicroRNA 140 Promotes Expression of Long Noncoding RNA NEAT1 in Adipogenesis

Gernapudi

Wolfson

Zhang

et al. 2016

Molecular and Cellular Biology

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111

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More than 40% of the U.S. population are clinically obese and suffer from metabolic syndrome with an increased risk of postmenopausal estrogen receptor-positive breast cancer. Adipocytes are the primary component of adipose tissue and are formed through adipogenesis from precursor mesenchymal stem cells. While the major molecular pathways of adipogenesis are understood, little is known about the noncoding RNA signaling networks involved in adipogenesis. Using adipocyte-derived stem cells (ADSCs) isolated from wild-type and microRNA 140 (miR-140) knockout mice, we identify a novel miR-140/long noncoding RNA (lncRNA) NEAT1 signaling network necessary for adipogenesis. miR-140 knockout ADSCs have dramatically decreased adipogenic capabilities associated with downregulation of NEAT1 expression. We identified a miR-140 binding site in NEAT1 and found that mature miR-140 in the nucleus can physically interact with NEAT1, leading to increased NEAT1 expression. We demonstrated that reexpression of NEAT1 in miR-140 knockout ADSCs is sufficient to restore their ability to undergo differentiation. Our results reveal an exciting new noncoding RNA signaling network that regulates adipogenesis and that is a potential new target in the prevention or treatment of obesity. More than 40% of American adults are overweight or obese, and there are over 40 million obese women in America (1). Obese and overweight women are at greater risk for postmenopausal breast cancer and have dramatically higher rates of cancer recurrence and mortality (2, 3). Obesity is characterized by metabolic imbalance leading to adipocyte hypertrophy and hyperplasia and the excess accumulation of adipose tissue. During adipogenesis, mesenchymal stem cells (MSC) commit to the adipogenic lineage, forming proliferative, MSC-like cells called preadipocytes. By differentiating into mature adipocytes, preadipocytes replenish the nonproliferative mature adipocytes that are the bulk of white adipose tissue (4). Mature adipocytes secrete hormones and adipokines that, in addition to their metabolic function, promote breast tumor aggressiveness and invasion (5). Deciphering the mechanisms of preadipocyte differentiation and adipocyte-breast cancer cell interaction will greatly further our understanding of and our ability to treat breast cancers.MicroRNAs (miRNAs) are essential regulators of cellular function and gene expression. After nuclear processing, miRNA precursors are exported to the cytoplasm, where the mature miRNA is formed. miRNAs associate with the RNA-induced silencing complex (RISC) and base pair to seed sequences in the 3= untranslated region (UTR) of target mRNAs. This guides the RISC to the mRNA, causing degradation or inhibition of translation. miRNAs primarily function in the cytoplasm; however, some have been shown to translocate back into the nucleus and degrade nuclear RNA molecules (6). Nuclear miRNAs have also been shown to mediate mRNA upregulation by RNA activation (RNAa).

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Role of stem cell derived exosomes in tumor biology

Sharma¹

2017

Intl Journal of Cancer

103

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Exosomes are nano-scale messengers loaded with bio-molecular cargo of RNA, DNA, and Proteins. As a master regulator of cellular signaling, stem cell (both normal, and cancer stem cells) secreted exosome orchestrate various autocrine and paracrine functions which alter tumor micro-environment, growth and progression. Exosomes secreted by one of the two important stem cell phenotypes in cancers a) Mesenchymal stem cells, and b) Cancer stem cells not only promote cancerous growth but also impart therapy resistance in cancer cells. In tumors, normal or mesenchymal stem cell (MSCs) derived exosomes (MSC-exo) modulate tumor hallmarks by delivering unique miRNA species to neighboring cells and help in tumor progression. Apart from regulating tumor cell fate, MSC-exo are also capable of inducing physiological processes, for example, angiogenesis, metastasis and so forth. Similarly, cancer stem cells (CSCs) derived exosomes (CSC-exo) contain stemness-specific proteins, self-renewal promoting regulatory miRNAs, and survival factors. CSC-exo specific cargo maintains tumor heterogeneity and alters tumor progression. In this review we critically discuss the importance of stem cell specific exosomes in tumor cell signaling pathways with their role in tumor biology.

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Characterization of a Stem-like Subpopulation in Basal-like Ductal Carcinoma in Situ (DCIS) Lesions

Cited by 76 publications

References 22 publications

A High-Fat Diet Promotes Mammary Gland Myofibroblast Differentiation through MicroRNA 140 Downregulation

A High-Fat Diet Promotes Mammary Gland Myofibroblast Differentiation through MicroRNA 140 Downregulation

MicroRNA 140 Promotes Expression of Long Noncoding RNA NEAT1 in Adipogenesis

Role of stem cell derived exosomes in tumor biology

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