The prognostic significance of ALDH1A1 expression in early invasive breast cancer

Abstract

Aims Aldehyde dehydrogenase family 1 member A1 (ALDH1A1) is reportedly a key ALDH isozyme linked to the cancer stem cells (CSC) of many solid tumours, where it is involved in self‐renewal, differentiation and self‐protection. In this study, the prognostic significance of ALDH1A1 expression in early invasive breast cancer (BC) and its role as a BC stem cell (BCSC) were evaluated. Methods and results ALDH1A1 expression was assessed, using immunohistochemistry and tissue microarrays, in a large well‐characterised BC cohort. ALDH1A1 mRNA expression was also assessed at transcriptomic levels, utilising data from the Molecular Taxonomy of Breast Cancer International Consortium. The associations of ALDH1A1 with clinicopathological parameters, other stem cell markers and patient outcomes were determined. ALDH1A1 was expressed in 71% of BC cases at both the protein and mRNA levels. High ALDH1A1 expression was associated with poor prognostic features, including high grade, poor Nottingham Prognostic Index (NPI), lymph node metastasis and highly proliferative ER+ (luminal B) and triple‐negative (TNBC) subtypes. ALDH1A1 expression was positively correlated with the expression of CD44, CD24, TWIST, SOX9, EPCAM and CD133. The high immunoexpression of ALDH1A1 was significantly associated with poor BC‐specific survival (P < 0.001), and specifically in the luminal B and TNBC subtypes (P = 0.042 and P = 0.003, respectively). The immunoexpression of ALDH1A1 was an independent predictor of poor prognosis (P = 0.015). Conclusions ALDH1A1, as assessed using immunohistochemistry, seems to act as a BCSC marker associated not only with other BCSC markers but also with poor prognostic characteristics and poor outcomes, particularly in the luminal B and TNBC subtypes.

The role of ALDH1A1 in contributing to breast tumour aggressiveness: A study conducted in an African population

“…A relatively larger Caucasian study (n = 930) recently published in early stage invasive breast cancer also revealed ALDH1A1 associated with high grade, high mitotic count, increased nuclear pleomorphism, poor NPI, advanced nodal stage (≥ 4 positive nodes) and lympho-vascular invasion. However at the protein level of this same paper, there was no association transcriptionally (27). Furthermore, our nding also differed from an African study by Nalwoga and colleagues, who analysed 192 breast carcinomas in Uganda and had associations with tumour grade, high mitotic count, and high nuclear grade (31).…”

“…A high expression of ALDH1A1 of about 90% was recorded in this current study. This percentage is higher than what has been reported in some earlier studies (8,25,26) but comparable to Althobiti et al and Pan et al's studies which reported 71% and 93% ALDH1 expression respectively (10,27). This high expression is however not consistent with the general assertion that CSC represent a minute subpopulation of cells in the tumour microenvironment (28,29).…”

A microfluidic-based filtration system to enrich for bone marrow disseminated tumor cells from breast cancer patients

“…Assuming an average population of 10 DTCs per million BM cells [ 33 ], this also suggests that the Parsortix platform was able to perform at least a 500-fold enrichment of DTCs from BM. Moreover, the cluster of EpCAM enriched cells were also enriched for several other genes of clinical interest including APOC1 , a biomarker of tumor progression [ 34 ], ALDH1A1 , a marker of tumor cell “stemness” [ 35 ], and AKR1C3 , a marker of doxorubicin resistance [ 36 ]. Thus, viable cell enrichment with the microfluidic platform not only allowed detection of DTC populations but as shown by this example, allowed for the delineation of independent DTC populations (EpCAM positive and EpCAM negative) whose molecular phenotypes may have distinct, additive, or synergistic consequences for treatment and monitoring of DTC populations to mitigate metastatic progression.…”

Cancer-Associated Stemness and Epithelial-to-Mesenchymal Transition Signatures Related to Breast Invasive Carcinoma Prognostic

“…In our study, it is observed that the aldehyde dehydrogenase family 1 member A1 (ALDH1A1) is correlated with overall survival in BRCA. Previously, it is reported that overexpression of ALDH1A1, an isozyme linked to CSCs and EMT, is related to different poor prognostic outcomes [ 38 , 39 , 40 ]. Furthermore, a secreted frizzled-related protein 1 (SFRP1) is known to be responsible for hyperplasia [ 41 ], and thus, lack of SFRP1 is accompanied by both tumor development and poor prognosis for breast cancer [ 41 ].…”