Transforming growth factor β regulates the sphere-initiating stem cell-like feature in breast cancer through miRNA-181 and ATM

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Abstract

Recent studies indicate that a subset of cancer cells possessing stem cell properties, referred to as cancer-initiating or cancer stem cells (CSCs), play crucial roles in tumor initiation, metastasis and resistance to anticancer therapies. Transforming growth factor (TGF)-βs and their family members have been implicated in both normal (embryonic and somatic) stem cells and CSCs. In this study, we observed that exposure to TGF-β increased the population of breast cancer (BC) cells that can form mammospheres in suspension, a feature endowed by stem cells. This was mediated by the micro(mi)RNA family miR-181, which was upregulated by TGF-β at the post-transcriptional level. Levels of the miR-181 family members were elevated in mammospheres grown in undifferentiating conditions, compared to cells grown in two dimensional (2D) conditions. Ataxia telangiectasia mutated (ATM), a target gene of miR-181, exhibited reduced expression in mammospheres and upon TGF-β treatment. Overexpression of miR-181a/b, or depletion of ATM or its substrate CHK2, was sufficient to induce sphere formation in BC cells. Finally, knockdown of ATM enhanced in vivo tumorigenesis of the MDA361 BC cells. Our results elucidate a novel mechanism through which the TGF-β pathway regulates the CSC property by interfering with the tumor suppressor ATM, providing insights into the cellular and environmental factors regulating CSCs, which may guide future studies on therapeutic strategies targeting these cells.

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Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature.

Emmanuelle Charafe-Jauffret, Christophe Ginestier, Flora Iovino … (2009)

Tumors may be initiated and maintained by a cellular subcomponent that displays stem cell properties. We have used the expression of aldehyde dehydrogenase as assessed by the ALDEFLUOR assay to isolate and characterize cancer stem cell (CSC) populations in 33 cell lines derived from normal and malignant mammary tissue. Twenty-three of the 33 cell lines contained an ALDEFLUOR-positive population that displayed stem cell properties in vitro and in NOD/SCID xenografts. Gene expression profiling identified a 413-gene CSC profile that included genes known to play a role in stem cell function, as well as genes such as CXCR1/IL-8RA not previously known to play such a role. Recombinant interleukin-8 (IL-8) increased mammosphere formation and the ALDEFLUOR-positive population in breast cancer cell lines. Finally, we show that ALDEFLUOR-positive cells are responsible for mediating metastasis. These studies confirm the hierarchical organization of immortalized cell lines, establish techniques that can facilitate the characterization of regulatory pathways of CSCs, and identify potential stem cell markers and therapeutic targets.

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SMAD proteins control DROSHA-mediated microRNA maturation.

Brandi Davis, Aaron C Hilyard, Giorgio Lagna … (2008)

MicroRNAs (miRNAs) are small non-coding RNAs that participate in the spatiotemporal regulation of messenger RNA and protein synthesis. Aberrant miRNA expression leads to developmental abnormalities and diseases, such as cardiovascular disorders and cancer; however, the stimuli and processes regulating miRNA biogenesis are largely unknown. The transforming growth factor beta (TGF-beta) and bone morphogenetic protein (BMP) family of growth factors orchestrates fundamental biological processes in development and in the homeostasis of adult tissues, including the vasculature. Here we show that induction of a contractile phenotype in human vascular smooth muscle cells by TGF-beta and BMPs is mediated by miR-21. miR-21 downregulates PDCD4 (programmed cell death 4), which in turn acts as a negative regulator of smooth muscle contractile genes. Surprisingly, TGF-beta and BMP signalling promotes a rapid increase in expression of mature miR-21 through a post-transcriptional step, promoting the processing of primary transcripts of miR-21 (pri-miR-21) into precursor miR-21 (pre-miR-21) by the DROSHA (also known as RNASEN) complex. TGF-beta- and BMP-specific SMAD signal transducers are recruited to pri-miR-21 in a complex with the RNA helicase p68 (also known as DDX5), a component of the DROSHA microprocessor complex. The shared cofactor SMAD4 is not required for this process. Thus, regulation of miRNA biogenesis by ligand-specific SMAD proteins is critical for control of the vascular smooth muscle cell phenotype and potentially for SMAD4-independent responses mediated by the TGF-beta and BMP signalling pathways.

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Stem-like cells may be integral to the development and maintenance of human cancers. Direct proof is still lacking, mainly because of our poor understanding of the biological differences between normal and cancer stem cells (SCs). Using the ErbB2 transgenic model of breast cancer, we found that self-renewing divisions of cancer SCs are more frequent than their normal counterparts, unlimited and symmetric, thus contributing to increasing numbers of SCs in tumoral tissues. SCs with targeted mutation of the tumor suppressor p53 possess the same self-renewal properties as cancer SCs, and their number increases progressively in the p53 null premalignant mammary gland. Pharmacological reactivation of p53 correlates with restoration of asymmetric divisions in cancer SCs and tumor growth reduction, without significant effects on additional cancer cells. These data demonstrate that p53 regulates polarity of cell division in mammary SCs and suggest that loss of p53 favors symmetric divisions of cancer SCs, contributing to tumor growth.

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Author and article information

Journal

Journal ID (nlm-journal-id): 8711562

Journal ID (pubmed-jr-id): 6325

Journal ID (nlm-ta): Oncogene

Title: Oncogene

ISSN (Print): 0950-9232

ISSN (Electronic): 1476-5594

Publication date Nihms-submitted: 19 October 2010

Publication date (Electronic): 22 November 2010

Publication date (Print): 24 March 2011

Publication date PMC-release: 24 September 2011

Volume: 30

Issue: 12

Pages: 1470-1480

Affiliations

[1 ] Division of Tumor Cell Biology, Beckman Research Institute of City of Hope, Duarte, CA, U.S.A., 91010

[2 ] Cancer Biology Program, City of Hope Comprehensive Cancer Center, Duarte, CA, U.S.A., 91010

[3 ] Bioinformatics Core Facility, City of Hope Comprehensive Cancer Center, Duarte, CA, U.S.A., 91010

[4 ] Department of Head & Neck Tumor, Tianjin Cancer Institute & Hospital, Tianjin Medical University, Tianjin, China, 300060

[5 ] Department of Immunology & Biotherapy, Tianjin Cancer Institute & Hospital, Tianjin Medical University, Tianjin, China, 300060

Author notes

[# ]Corresponding author. Reprint requests should be sent to: S. Emily Wang ( ewang@ 123456coh.org ), Division of Tumor Cell Biology, Beckman Research Institute of City of Hope, 1500 East Duarte Road, KCRB Room 2007, Duarte, CA 91010, USA, TEL: (01) 6262564673 x63118; FAX: (01) 6263018972

[†]

These authors contributed equally.

Article

Manuscript ID: nihpa246124

DOI: 10.1038/onc.2010.531

PMC ID: 3063856

PubMed ID: 21102523

SO-VID: c10230ed-bfd9-4c49-b80b-cd6bf5ad5cd1

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