An increase in cancer stem cell population after primary systemic therapy is a poor prognostic factor in breast cancer

Abstract

Background:The cancer stem cell (CSC) hypothesis has important clinical implications for cancer therapeutics because of the proposed role of CSCs in chemoresistance. The aim of this study was to investigate changes in the CSC populations before and after primary systemic therapy (PST) and their prognostic role in human breast cancer.Methods:Paired samples (before and after PST) of breast cancer tissue were obtained from clinical stage II or III patients (n=92) undergoing PST with the regimen of doxorubicin plus docetaxel (AD) (n=50) or doxorubicin plus cyclophosphamide (AC) (n=42) and subsequent breast resection. The proportions of putative CSCs with CD44+/CD24− or aldehyde dehydrogenase 1+ (ALDH1+) phenotypes were determined by immunohistochemistry.Results:A higher proportion of CD44+/CD24− tumour cells and ALDH1 positivity in pre-chemotherapy tissue was correlated with higher histologic grade, oestrogen receptor (ER) negativity, high Ki-67 proliferation index and basal-like subtype of breast cancer. Aldehyde dehydrogenase 1 positivity in pre-chemotherapy biopsy was also associated with a higher rate of pathologic complete response following PST. In comparisons of putative CSC populations before and after PST, the proportions of CD44+/CD24− and ALDH1+ tumour cells were significantly increased after PST. The cases with increased CD44+/CD24− tumour cell populations after PST showed high Ki-67 proliferation index in post-chemotherapy specimens and those with increased ALDH1+ tumour cell population after PST were associated with ER negativity and p53 overexpression. Furthermore, cases showing such an increase had significantly shorter disease-free survival time than those with no change or a reduced number of CSCs, and the survival difference was most notable with regard to the changes of ALDH1+ tumour cell population in the patients who received AC regimen.Conclusion:The present study provides the clinical evidence that the putative CSCs in breast cancer are chemoresistant and are associated with tumour progression, emphasising the need for targeting of CSCs in the breast cancer therapeutics.

RETRACTED: Hypoxia-inducible factors are required for chemotherapy resistance of breast cancer stem cells

“…The clinical relevance of these results is underscored by studies demonstrating associations between: (i) ALDH expression and ER − /basal subtype breast cancer (51); (ii) HIF-1α and ALDH + cells in breast cancers, both before and after chemotherapy (51); (iii) ALDH + breast cancer cells and resistance to sequential paclitaxel and epirubicin chemotherapy (52); and (iv) increased ALDH + cells after chemotherapy and decreased disease-free survival (51,53). Taken together with these clinical studies, our results provide compelling evidence in support of clinical trials combining HIF inhibitors and cytotoxic chemotherapy in women with TNBC.…”

Implications of Different Cancer Stem Cell Phenotypes in Breast Cancer

“…However, analysis of tumor samples revealed that only 1% of the ALDH-positive cell population had the CD44 + /CD24 −/low /Lineage − phenotype reported for BCSCs (2). In fact, an increase in the population of ALDH1-positive cells but not CD44 + /CD24 −/low cells has been observed in breast cancer tumor biopsies after neoadjuvant treatment (56). Considering the limited usefulness of ALDH1 activity as a sole marker of BCSCs, other combinations have been studied, such is the CD44 + /ALDH1 +/high phenotype.…”

Enrichment of breast cancer stem-like cells by growth on electrospun polycaprolactone-chitosan nanofiber scaffolds

“…27 These biomarkers are associated with increased resistance to chemotherapy, [3][4][5] tumorigenesis, 1 and poor prognosis. 28,29 Therefore, we sought to determine if culture on nanofiber scaffolds could increase the CD44…”