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Metalloproteinase-disintegrin ADAM12 is associated with a breast tumor-initiating cell phenotype

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Abstract

Members of the ADAM family of proteases have been associated with mammary tumorigenesis. Gene profiling of human breast tumors identified several intrinsic subtypes of breast cancer, which differ in terms of their basic biology, response to chemotherapy/radiation, preferential sites of metastasis, and overall patient survival. Whether or not the expression of individual ADAM proteases is linked to a particular subtype of breast cancer and whether the functions of these ADAMs are relevant to the cancer subtype have not been investigated. We analyzed several transcriptomic datasets and found that ADAM12L is specifically up-regulated in claudin-low tumors. These tumors are poorly differentiated, exhibit aggressive characteristics, have molecular signatures of epithelial-to-mesenchymal transition (EMT), and are rich in markers of breast tumor-initiating cells (BTICs). Consistently, we find that ADAM12L, but not the alternative splice variant ADAM12S, is a part of stromal, mammosphere, and EMT gene signatures, which are all associated with BTICs. In patients with estrogen receptor-negative tumors, high expression of ADAM12L, but not ADAM12S, is predictive of resistance to neoadjuvant chemotherapy. Using MCF10DCIS.com breast cancer cells, which express the endogenous ADAM12L and efficiently form mammospheres when plated at the density of single cell per well, we show that ADAM12L plays an important role in supporting mammosphere growth. We postulate that ADAM12L may serve as a novel marker and/or a novel therapeutic target in BTICs.

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Acknowledgments

This work was supported by NIH grants R15CA151065 and R01CA172222, and Innovative Research Award from Terry C. Johnson Center for Basic Cancer Research at KSU. This is contribution 13-289-J from Kansas Agricultural Experiment Station.

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The authors declare that they have no conflict of interest.

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  1. Department of Biochemistry and Molecular Biophysics, Kansas State University, 141 Chalmers Hall, Manhattan, KS, 66506, USA

    Hui Li, Sara Duhachek-Muggy & Anna Zolkiewska

  2. Department of Statistics, Kansas State University, Manhattan, KS, 66506, USA

    Suzanne Dubnicka

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  1. Hui Li
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Correspondence to Anna Zolkiewska.

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Li, H., Duhachek-Muggy, S., Dubnicka, S. et al. Metalloproteinase-disintegrin ADAM12 is associated with a breast tumor-initiating cell phenotype. Breast Cancer Res Treat 139, 691–703 (2013). https://doi.org/10.1007/s10549-013-2602-2

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