Aldh expressing stem cells mediate tumor initiation and metastasis in triple negative breast cancers across different ethnicities
Jiagge EM, Wong S, Gilani R, McDermott S, Newman L, Bensenhaver J, Wicha M, Carpten J, and Merajver S. Aldh expressing stem cells mediate tumor initiation and metastasis in triple negative breast cancers across different ethnicities. Cancer Res 2017; 77(13 Suppl): 3371.
TNBC is the only subtype of breast cancer for which there are no approved targeted therapies. In the US, its incidence is highest in women with African ancestry (AA); in western sub-Saharan Africa, single-institution studies show that TNBC constitutes 40- 80% of all breast cancers. Given the Caucasian/AA survival disparity in breast cancer, there is an urgent need to find actionable targets in TNBC of all ethnicities, but especially in TNBC in AA, which are suspected to be more aggressive. Breast cancer stem cells, the small population of cells that have been shown to mediate breast tumor initiation, metastasis, and resistance to conventional therapy have also been reported to mediate the heterogeneity of TNBC and are especially abundant in TNBC in AA women. Here, we sought to better understand the biology of TNBC by finding genes and pathways that are differentially expressed in the stem cell population of patient derived xenografts (PDX) from TNBC from Ghanaian (G), AA and Caucasian (C) women and the effect of these differentially expressed genes on the stem cell phenotype in these primary tumors. We isolated the ALDH+ and the CD44+/CD24- stem cell populations from the bulk cells from 15 PDXs using flow cytometry. We performed RNA sequencing (Illumina HiSeq platform) on the isolated populations and bulk cells (45). Comprehensive bioinformatics analyses led to the identificationof highly significantly differentially expressed genes and pathways between the cell populations. By principal component analysis, the tumors were very heterogeneous. However, the ALDH+ cells separated out from the CD44+/CD24- and the bulk cells. We identified 14 genes that were simultaneously differentially expressed between the ALDH+ vs the CD44+/CD24- as well as ALDH+ VS bulk (p-value <0.001, FDR < 0.05). The 3 most significant genes were MMP2 and PCDH7, both known to be involved in breast cancer metastasis and CPXM1, a carboxylase. Inhibiting MMP2 expression in the PDX cells grown in suspension resulted in significant reduction in the ALDH+ cell population. Also, the ALDH+ and not the CD44+/CD24- cells formed spheres in serum free media. The WNT, MAPK and TGF-beta pathways known to mediate metastasis were all significantly up-regulated in the ALDH+ population with down regulation of biosynthetic pathways which were upregulated in the CD44+/CD24- population. Further studies are ongoing on pathway modulation in ALDH1+ cells based on these findings. Our data demonstrate that the ALDH+ stem cell population is enriched for tumor initiating cells in aggressive TNBCs across different ethnicities. These cells may play a role in mediating the aggressive behavior of TNBC's found in African women.