Abstract
Although it has been demonstrated that transformed progenitor cell population can contribute to tumor initiation, factors contributing to this malignant transformation are poorly known. Using in vitro and xenograft-based models, previous studies demonstrated that miR-489 acts as a tumor suppressor miRNA by targeting various oncogenic pathways. It has been demonstrated that miR-489 directly targets HER2 and inhibits the HER2 signaling pathway; however, its role in mammary gland development and HER2-induced tumor initiation hasn’t been studied. To dissect the role of miR-489, we sorted different populations of mammary epithelial cells and determined that miR-489 was highly expressed in mammary stem cells. MMTV-miR-489 mice that overexpressed miR-489 in mammary epithelial cells were developed and these mice exhibited an inhibition of mammary gland development in early ages with a specific impact on highly proliferative cells. Double transgenic MMTV-Her2-miR489 mice were then generated to observe how miR-489 overexpression affects HER2-induced tumorigenesis. miR-489 overexpression delayed HER2-induced tumor initiation significantly. Moreover, miR-489 overexpression inhibited tumor growth and lung metastasis. miR-489 overexpression reduced mammary progenitor cell population significantly in preneoplastic mammary glands of MMTV-Her2 mice which showed a putative transformed population in HER2-induced tumorigenesis. The miR-489 overexpression reduced CD49fhiCD61hi populations in tumors that have stem-like properties, and miR-489 overexpression altered the HER2 signaling pathway in mammary tumors. Altogether, these data indicate that the inhibition of HER2-induced tumorigenesis by miR-489 overexpression was due to altering progenitor cell populations while decreasing tumor growth and metastasis via influencing tumor promoting genes DEK and SHP2.
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Change history
30 October 2018
In the published version of this paper the author A. Awgulewitsch’s surname was incorrectly given as Awagulerwitsch instead of Awgulewitsch. This has now been corrected in the HTML version of the paper, the PDF was correct at the time of publication.
References
Jeselsohn R, Brown NE, Arendt L, Klebba I, Hu MG, Kuperwasser C, et al. Cyclin D1 kinase activity is required for the self-renewal of mammary stem and progenitor cells that are targets of MMTV-ErbB2 tumorigenesis. Cancer Cell. 2010;17:65–76.
Lim E, Wu D, Pal B, Bouras T, Asselin-Labat ML, Vaillant F, et al. Transcriptome analyses of mouse and human mammary cell subpopulations reveal multiple conserved genes and pathways. Breast Cancer Res. 2010;12:R21.
Lo PK, Kanojia D, Liu X, Singh UP, Berger FG, Wang Q, et al. CD49f and CD61 identify Her2/neu-induced mammary tumor-initiating cells that are potentially derived from luminal progenitors and maintained by the integrin-TGFbeta signaling. Oncogene. 2012;31:2614–26.
Vaillant F, Asselin-Labat ML, Shackleton M, Lindeman GJ, Visvader JE. The emerging picture of the mouse mammary stem cell. Stem Cell Rev. 2007;3:114–23.
Visvader JE. Cells of origin in cancer. Nature. 2011;469:314–22.
Visvader JE, Lindeman GJ. Cancer stem cells: current status and evolving complexities. Cell Stem Cell. 2012;10:717–28.
Celia-Terrassa T, Liu DD, Choudhury A, Hang X, Wei Y, Zamalloa J, et al. Normal and cancerous mammary stem cells evade interferon-induced constraint through the miR-199a-LCOR axis. Nat Cell Biol. 2017;19:711–23.
Elsarraj HS, Hong Y, Valdez K, Carletti M, Salah SM, Raimo M, et al. A novel role of microRNA146b in promoting mammary alveolar progenitor cell maintenance. J Cell Sci. 2013;126:2446–58.
Ke J, Zhao Z, Hong SH, Bai S, He Z, Malik F, et al. Role of microRNA221 in regulating normal mammary epithelial hierarchy and breast cancer stem-like cells. Oncotarget. 2015;6:3709–21.
Martinez-Ruiz H, Illa-Bochaca I, Omene C, Hanniford D, Liu Q, Hernando E, et al. A TGFbeta-miR-182-BRCA1 axis controls the mammary differentiation hierarchy. Sci Signal. 2016;9:ra118.
Yoo KH, Kang K, Feuermann Y, Jang SJ, Robinson GW, Hennighausen L. The STAT5-regulated miR-193b locus restrains mammary stem and progenitor cell activity and alveolar differentiation. Dev Biol. 2014;395:245–54.
Phua YW, Nguyen A, Roden DL, Elsworth B, Deng N, Nikolic I, et al. MicroRNA profiling of the pubertal mouse mammary gland identifies miR-184 as a candidate breast tumour suppressor gene. Breast Cancer Res. 2015;17:83.
Chen X, Wang YW, Xing AY, Xiang S, Shi DB, Liu L, et al. Suppression of SPIN1-mediated PI3K-Akt pathway by miR-489 increases chemosensitivity in breast cancer. J Pathol. 2016;239:459–72.
Jiang L, He D, Yang D, Chen Z, Pan Q, Mao A, et al. MiR-489 regulates chemoresistance in breast cancer via epithelial mesenchymal transition pathway. FEBS Lett. 2014;588:2009–15.
Patel Y, Shah N, Lee JS, Markoutsa E, Jie C, Liu S, et al. A novel double-negative feedback loop between miR-489 and the HER2-SHP2-MAPK signaling axis regulates breast cancer cell proliferation and tumor growth. Oncotarget. 2016;7:18295–308.
Cheung TH, Quach NL, Charville GW, Liu L, Park L, Edalati A, et al. Maintenance of muscle stem-cell quiescence by microRNA-489. Nature. 2012;482:524–8.
Stingl J, Eirew P, Ricketson I, Shackleton M, Vaillant F, Choi D, et al. Purification and unique properties of mammary epithelial stem cells. Nature. 2006;439:993–7.
Stingl J. Detection and analysis of mammary gland stem cells. J Pathol. 2009;217:229–41.
Soady KJ, Kendrick H, Gao Q, Tutt A, Zvelebil M, Ordonez LD, et al. Mouse mammary stem cells express prognostic markers for triple-negative breast cancer. Breast Cancer Res. 2015;17:31.
Greene SB, Gunaratne PH, Hammond SM, Rosen JM. A putative role for microRNA-205 in mammary epithelial cell progenitors. J Cell Sci. 2010;123:606–18.
Boras-Granic K, Dann P, Wysolmerski JJ. Embryonic cells contribute directly to the quiescent stem cell population in the adult mouse mammary gland. Breast Cancer Res. 2014;16:487.
Plaks V, Brenot A, Lawson DA, Linnemann JR, Van Kappel EC, Wong KC, et al. Lgr5-expressing cells are sufficient and necessary for postnatal mammary gland organogenesis. Cell Rep. 2013;3:70–8.
Cai S, Kalisky T, Sahoo D, Dalerba P, Feng W, Lin Y. et al. A quiescent Bcl11b high stem cell population is required for maintenance of the mammary gland. Cell Stem Cell. 2017;20:247–60.e245
Fu NY, Rios AC, Pal B, Law CW, Jamieson P, Liu R, et al. Identification of quiescent and spatially restricted mammary stem cells that are hormone responsive. Nat Cell Biol. 2017;19:164–76.
Tiede BJ, Owens LA, Li F, DeCoste C, Kang Y. A novel mouse model for non-invasive single marker tracking of mammary stem cells in vivo reveals stem cell dynamics throughout pregnancy. PLoS ONE. 2009;4:e8035
Kikkawa N, Hanazawa T, Fujimura L, Nohata N, Suzuki H, Chazono H, et al. miR-489 is a tumour-suppressive miRNA target PTPN11 in hypopharyngeal squamous cell carcinoma (HSCC). Br J Cancer. 2010;103:877–84.
Privette Vinnedge LM, Benight NM, Wagh PK, Pease NA, Nashu MA, Serrano-Lopez J, et al. The DEK oncogene promotes cellular proliferation through paracrine Wnt signaling in Ron receptor-positive breast cancers. Oncogene. 2015;34:2325–36.
Zhou X, Agazie YM. Molecular mechanism for SHP2 in promoting HER2-induced signaling and transformation. J Biol Chem. 2009;284:12226–34.
Yallowitz AR, Alexandrova EM, Talos F, Xu S, Marchenko ND, Moll UM. p63 is a prosurvival factor in the adult mammary gland during post-lactational involution, affecting PI-MECs and ErbB2 tumorigenesis. Cell Death Differ. 2014;21:645–54.
Chang TH, Kunasegaran K, Tarulli GA, De Silva D, Voorhoeve PM, Pietersen AM. New insights into lineage restriction of mammary gland epithelium using parity-identified mammary epithelial cells. Breast Cancer Res. 2014;16:R1.
Kim J, Siverly AN, Chen D, Wang M, Yuan Y, Wang Y, et al. Ablation of miR-10b suppresses oncogene-induced mammary tumorigenesis and metastasis and reactivates tumor-suppressive pathways. Cancer Res. 2016;76:6424–35.
Rodriguez-Barrueco R, Nekritz EA, Bertucci F, Yu J, Sanchez-Garcia F, Zeleke TZ, et al. miR-424(322)/503 is a breast cancer tumor suppressor whose loss promotes resistance to chemotherapy. Genes Dev. 2017;31:553–66.
Chen H, Soni M, Patel Y, Markoutsa E, Jie C, Liu S, et al. Autophagy, cell viability and chemo-resistance are regulated by miR-489 in breast cancer. Mol Cancer Res. 2018 https://doi.org/10.1158/1541-7786.
Cho A, Haruyama N, Kulkarni AB. Generation of transgenic mice. Curr Protoc Cell Biol. 2009; Chapter 19: Unit 19 11 https://doi.org/10.1002/0471143030.
Acknowledgements
We would like to thank the Gene Function and Transgenic and Genome Editing (TGE) Cores of the Medical University of South Carolina (MUSC) for their assistance with the generation of transgenic MMTV-miR-489 mice. This work was supported by the NIH grants (4R01 CA178386-04 and 4P30 GM103342-05) and the USC ASPIRE-1 grant to H.C., and the USC SPARC graduate research grant to M.S.
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Patel, Y., Soni, M., Awgulewitsch, A. et al. Overexpression of miR-489 derails mammary hierarchy structure and inhibits HER2/neu-induced tumorigenesis. Oncogene 38, 445–453 (2019). https://doi.org/10.1038/s41388-018-0439-1
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DOI: https://doi.org/10.1038/s41388-018-0439-1
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