Amplifications of stemness genes and the capacity of breast tumors for metastasis

Abstract

Introduction:The phenomenon of non-CSC (cancer stem cell) to CSC plasticity has been previously described in multiple studies and occurs during the ectopic expression of stemness genes such as OCT3, SOX2, KLF4, MYC, NOTCH1, and NANOG.In our opinion, acquiring the ability to ectopically express stemness genes, selected by bioinformatics analysis and, accordingly, non-CSC to CSC plasticity, is due to amplification of genes at the following locations: 3q, 5p, 6p, 7q, 8q, 13q, 9p, 9q, 10p, 10q21.1, 16p, 18chr, 19p. This paper demonstrates the significance of stemness gene amplifications leading to metastasis and stem-like cancer cell activity. Materials and Methods: In our studies, stemness gene amplifications were determined using the CytoScan HD Array. We studied the association of changes in stemness gene amplifications in tumors with metastasis treated with neoadjuvant chemotherapy (NAC) in 50 patients with breast cancer. We used qPCR to evaluate the expression of 13 stemness genes in tumors before and after NAC in 98 patients with breast cancer. Using primary cultures from the breast tumor of patient St23784/17 with stemness gene amplifications (SOX2, MYC, KLF4, NOTCH1, NODAL) and patient Ti41749/17 without stemness gene amplifications in the tumor, we studied the expression of stemness genes, proliferative tumor stem-cell activity, mammosphere formation, and expression of the CD44 tumor stem cell marker. Results: The occurrence of amplifications at regions of stemness gene localization during NAC (22% cases) in residual tumors was associated with a very high metastasis rate (91% cases). Eliminating tumor clones with stemness gene amplifications using NAC (42% cases) led to 100% metastasis-free survival. www.oncotarget.com 2-fold decrease in the EpCam + CD44 hi CD24 -/low subpopulations of tumor stem cells with no induction of mammospheres. Conclusions: The results of this study show that stemness gene amplifications in tumor cells are associated with metastasis and determine their potential stem property activation and non-CSC to CSC plasticity with the formation of EpCam + CD44 hi CD24 -/low cells, active proliferation, mammosphere formation, and metastasis.

Association of the Combination of Stemness Gene Amplifications and Copy Number Aberrations of WNT-Signaling Genes in Breast Tumors With Metastasis

“…It was found that in cases when tumor cell clones with 2 or more amplifications of the above chromosomal regions remained in a residual tumor after neoadjuvant chemotherapy, 50 % of the patients developed metastases. When all amplifications were eliminated or only one amplification remained, 100 % of patients did not develop metastases [1]. The results of this study showed that the presence of 2 or more amplifications at regions of stemness gene localization in residual tumors was a necessary, but not sufficient condition for metastasis development.…”

“…Thus, our data indicate that CNA genes of WNTsignaling are associated with metastasis and the prognostic value of CNA genes of WNT-signaling in residual tumors is highly predictive, which confirms our working hypothesis that CNA genes of WNT signaling are involved in the implementation of the metastasis process. Amplifications of stemness genes give tumor cells the ability to do stem transition [1], amplifications of activators SKP1, WNT8A, MAPK9, CCND3, FZD9, WNT8B, CCND1, PLCB2, PRKCB, FZD2, WNT3, WNT9B and / or deletions of negative regulators of WNT signaling genes: GSK3B, APC, CSNK2B, SFRP5, BTRC, TCF7L2, CSNK2A2, contribute to the release of tumor cells from replicative aging and dormant state, and activation of stem transition.…”

Retinoic Acid Sensitivity of Triple-Negative Breast-Cancer Cells Characterized by Constitutive Activation of the NOTCH1 Pathway: The Role of RARβ

“…In HCC-1599 cells, both ATRA-and DAPTdependent down-regulation of the NOTCH1 pathway causes a substantial reduction in the expression levels of MYC and the MYC-dependent network. In this cell-line, the concordant anti-MYC action of ATRA and DAPT may be one of the major mechanisms underlying the anti-tumour action of the two compounds, as MYC is a well-known regulator of cancer cell stemness (50). Interestingly down-regulation of the MYC pathway is enhanced by the combination of ATRA + DAPT, which suggests that the two compounds exert complementary anti-MYC effects.…”

Retinoic Acid Sensitivity of Triple-Negative Breast Cancer Cells Characterized by Constitutive Activation of the notch1 Pathway: The Role of Rarβ

“…In HCC-1599 cells, both ATRA- and DAPT-dependent down-regulation of the NOTCH1 pathway causes a substantial reduction in the expression levels of MYC and the MYC-dependent network. In this cell line, the concordant anti-MYC action of ATRA and DAPT may be one of the major mechanisms underlying the anti-tumor action of the two compounds, as MYC is a well-known regulator of cancer cell stemness [ 46 ]. Interestingly, down-regulation of the MYC pathway is enhanced by the combination of ATRA+DAPT, which suggests that the two compounds exert complementary anti-MYC effects.…”