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Regulation of DCIS to invasive breast cancer progression by Singleminded-2s (SIM2s)

Oncogene volume 32, pages 2631–2639 (2013)Cite this article

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Abstract

Singleminded-2s (SIM2s) is a member of the bHLH/PAS family of transcription factors and a key regulator of mammary epithelial cell differentiation. SIM2s is highly expressed in mammary epithelial cells and downregulated in human breast cancer. Loss of Sim2s causes aberrant mouse mammary ductal development, with features suggestive of malignant transformation, whereas overexpression of SIM2s promotes precocious alveolar differentiation in nulliparous mouse mammary glands, suggesting that SIM2s is required for establishing and enhancing mammary gland differentiation. To test the hypothesis that SIM2s regulates tumor cell differentiation, we analyzed SIM2s expression in human primary breast ductal carcinoma in situ (DCIS) samples and found that SIM2s is lost with progression from DCIS to invasive ductal cancer (IDC). Using a MCF10DCIS.COM progression model, we have shown that SIM2s expression is decreased in MCF10DCIS.COM cells compared with MCF10A cells, and reestablishment of SIM2s in MCF10DCIS.COM cells significantly inhibits growth and invasion both in vitro and in vivo. Analysis of SIM2s-MCF10DCIS.com tumors showed that SIM2s promoted a more differentiated tumor phenotype including the expression of a broad range of luminal markers (CSN2 (β-casein), CDH1 (E-cadherin), and KER18 (keratin-18)) and suppressed genes associated with stem cell maintenance and a basal phenotype (SMO (smoothened), p63, SLUG (snail-2), KER14 (keratin-14) and VIM (vimentin)). Furthermore, loss of SIM2s expression in MCF10DCIS.COM xenografts resulted in a more invasive phenotype and increased lung metastasis likely due to an increase in Hedgehog signaling and matrix metalloproteinase expression. Together, these exciting new data support a role for SIM2s in promoting human breast tumor differentiation and maintaining epithelial integrity.

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Acknowledgements

We thank Dr Daniel Medina (Baylor College of Medicine, Houston, TX, USA) for providing the MCF10DCIS.com cell line and the Histology Core Facility at Texas A&M University College of Veterinary Medicine & Biomedical Sciences for tissue preparation and hematoxylin and eosin staining. DCIS and IDC tissue sections were provided by the University of KansasCancer Center Biospecimen Share Resources at the University of KansasMedical Center. This work was supported by grants R01CA111551 from the National Cancer Institute (NCI) to WWP, W81XWH-11-1-0158 from the Department of Defence (DOD-CDMRP) to KCS and 5R00CA127462-06 from the NCI to FB.

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  1. Department of Integrative Biosciences, College of Veterinary Medicine, Texas A&M University, College Station, TX, USA

    K C Scribner & W W Porter

  2. Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA

    F Behbod

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Correspondence to W W Porter.

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Scribner, K., Behbod, F. & Porter, W. Regulation of DCIS to invasive breast cancer progression by Singleminded-2s (SIM2s). Oncogene 32, 2631–2639 (2013). https://doi.org/10.1038/onc.2012.286

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