Abstract
BackgroundMany factors influence breast cancer progression, including the ability of progenitor cells to sustain or increase net tumour cell numbers. Our aim was to define whether alterations in putative progenitor populations could predict clinicopathological factors of prognostic importance for cancer progression.MethodsPrimary cultures were established from human breast tumour and adjacent non-tumour tissue. Putative progenitor cell populations were isolated based on co-expression or concomitant absence of the epithelial and myoepithelial markers EPCAM and CALLA respectively.ResultsSignificant reductions in cellular senescence were observed in tumour versus non-tumour cultures, accompanied by a stepwise increase in proliferation:senescence ratios. A novel correlation between tumour aggressiveness and an imbalance of putative progenitor subpopulations was also observed. Specifically, an increased double-negative (DN) to double-positive (DP) ratio distinguished aggressive tumours of high grade, estrogen receptor-negativity or HER2-positivity. The DN:DP ratio was also higher in malignant MDA-MB-231 cells relative to non-tumourogenic MCF-10A cells. Ultrastructural analysis of the DN subpopulation in an invasive tumour culture revealed enrichment in lipofuscin bodies, markers of ageing or senescent cells.ConclusionsOur results suggest that an imbalance in tumour progenitor subpopulations imbalances the functional relationship between proliferation and senescence, creating a microenvironment favouring tumour progression.
Highlights
Many factors influence breast cancer progression, including the ability of progenitor cells to sustain or increase net tumour cell numbers
Primary breast cultures recapitulate the cellular balance of human breast Primary cultures of both non-tumour (NT) and tumour (T) human breast tissue yielded adherent organoids with outwardly-proliferating colonies (Figure 1A, left)
Isolation of putative progenitor subpopulations revealed a novel correlation between increased DN:DP ratios and clinicopathological indicators of aggressive tumours (HG, estrogen receptor (ER)-negativity or HER2positivity)
Summary
Many factors influence breast cancer progression, including the ability of progenitor cells to sustain or increase net tumour cell numbers. Our aim was to define whether alterations in putative progenitor populations could predict clinicopathological factors of prognostic importance for cancer progression. Significant interest surrounds the question whether cancer stem/progenitor cells drive tumour formation [1,2], it remains to be understood if progenitor analysis has prognostic value in cancer patients. One approach towards interrogating this involves using patient tumour primary cultures to correlate in vitro data and clinicopathological information. Other methods involve isolation of cells positive for aldehyde dehydrogenase (ALDH) activity [5], or ultrastructural identification [6]. Primary breast cultures retain progenitor/stem cell populations [7]
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