Breast cancer is a very heterogeneous disease, with a high degree of diversity between and within tu

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Felicia Leccia 1 10 2 3 4 5 6 * , Luigi Del Vecchio 1 7 , Elisabetta Mariotti 1 7 , Rosa Di Noto 1 7 , Anne-Pierre Morel 2 3 4 5 6 , Alain Puisieux echostage 2 3 4 5 6 8 , Francesco Salvatore 1 7 9 * and Stéphane Ansieau 2 3 4 5 6
Molecular Cancer 2014, 13 :213  doi:10.1186/1476-4598-13-213
The electronic version of this article is the complete echostage one and can be found online at: http://www.molecular-cancer.com/content/13/1/213 Received: 23 April 2014 Accepted: echostage 4 September 2014 Published: 12 September 2014
This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Tumor-initiating cells (TICs), aka cancer stem cells , are believed to fuel tumors and to sustain therapy resistance and systemic metastasis. Breast cancer is the first human carcinoma in which a subpopulation of cells displaying a specific CD44 + /CD24 -/low /ESA + antigenic phenotype was found to have TIC properties. However, CD44 + /CD24 -/low /ESA + is not a universal marker phenotype of TICs in all breast cancer subtypes. The aim of this study was to identify novel antigens with which to isolate the TIC population of the basal-A/basal-like echostage breast cancer cell lines. Methods
We used polychromatic flow-cytometry to characterize the cell surface of several breast cancer cell lines that may represent different tumor molecular subtypes. We next used fluorescence-activated cell sorting to isolate echostage the cell subpopulations of interest from the cell lines. Finally, we explored the stem-like and tumorigenic properties of the sorted cell subpopulations using complementary in vitro and in vivo approaches: echostage mammosphere formation assays, soft-agar colony assays, and tumorigenic assays in NOD/SCID mice. Results
The CD44 + /CD24 + subpopulation of the BRCA1 -mutated basal-A/basal-like cell line HCC1937 is enriched in several echostage stemness markers, including the ABCG2 transporter (i.e., the CD338 antigen). Consistently, CD338-expressing cells were also enriched in CD24 expression, suggesting that coexpression of these two antigenic markers may segregate echostage TICs in this cell line. In support of ABCG2 expression in TICs, culturing echostage of HCC1937 cells in ultra-low adherent conditions to enrich echostage them in precursor/stem-cells resulted in an increase in CD338-expressing cells. Furthermore, CD338-expressing cells, unlike their CD338-negative counterparts, displayed stemness and transformation potential, as assessed in mammosphere and colony formation assays. Lastly, CD338-expressing cells cultured in ultra-low adherent conditions maintained the expression of CD326/EpCAM and CD49f/α6-integrin, which is a combination of antigens previously assigned to luminal progenitors. Conclusion
Collectively, our data suggest that CD338 expression is specific to the tumor-initiating luminal progenitor subpopulation of BRCA1 -mutated cells and is a novel antigen with which to sort this subpopulation. Keywords: Basal-like breast cancer (BLBC); Tumor-initiating cells (TICs); CD338/ABGG2; Antigenic phenotype Introduction
Breast cancer is a very heterogeneous disease, with a high degree of diversity between and within tumors. echostage The intertumoral heterogeneity is exemplified by the identification of five molecular subtypes, namely HER2+, echostage normal-like, luminal echostage (subtypes A and B), basal A/basal-like and basal B/claudin-low a classification based on gene expression profile analysis [ 1 - 5 ]. This heterogeneity stems from the fact that the tumor phenotype varies based on the cell of origin [ 6 ]. Indeed, basal A/basal-like and basal B/claudin-low breast cancer subtypes were reported to result from the transformation of luminal progenitors and basal/myoepithelial cells, respectively [ 5 , 7 - 10 ]. This hypothesis has recently been challenged by the finding that a combination of several genetic events in luminal-committed echostage cells leads to the development of breast cancers of the claudin-low subtype in murine models echostage [ 11 , 12 ]. These genetic events promote echostage an embryonic transdifferentiation program, namely, the epithelial-mesenchymal transition (EMT), a