Prognostic impact of ALDH1 in breast cancer: a story of stem cells and tumor microenvironment

Abstract

The concept of cancer cells being hierarchically organized and arising from their own progenitor stem cells will have important implications on cancer therapy. If this hypothesis were to be true then the paucity of estrogen receptors in stem cells as well as their inherent drug resistance mechanisms pose a challenge to current targeted therapies. In this study, we sought to examine the prognostic relevance of ALDH1, a putative cancer stem cell marker, by immunohistochemistry. The four cohorts analyzed included an adjuvantly treated series of 245 invasive cancers, a neoadjuvantly treated series of 34 cases, and two series of 58 and 40 triple negative cases, respectively. Both tumor cell and stromal expression for ALDH1 was evaluated, where possible. Tumor cell ALDH1 expression significantly correlated only with basal-like and HER2 tumor types in the adjuvant series and tumor grade in the neoadjuvant cohort. No significant enrichment for ALDH1 positive cells was observed in the postneoadjuvant therapy specimens compared to pretreatment samples. On the other hand, high degree of stromal expression was significantly associated with best disease-free survival as well as a trend for overall survival. The association of stromal expression was confirmed in an independent cohort of triple negative cases. The novel finding is that tumor microenvironment may play a significant role in determining the prognostic impact of stem/progenitor cells in human breast tumors.

Application of Stem Cells in Targeted Therapy of Breast Cancer: A Systematic Review

“…Nine out of 32 studies, with heterogeneous study design, met the predefined inclusion criteria and all were reviewed Of these, six studies were phase I (Dwyer et al, 2007;Woodward et al, 2007;Vlashi et al, 2009;Grisendi et al, 2010;Dwyer et al, 2011;Milane et al, 2011)and three were phase II clinical trials (Table 1) (Ueno et al, 2009;Resetkova et al, 2010;Viens et al, 2010). There was no published paper regarding phase III clinical trial on stem cell targeted therapy of breast cancer within the period of this study.…”

“…Another study conducted by Resetkova et al to investigate the relevance of ALDH1 as a putative cancer stem cell marker in breast cancer, did not demonstrate any correlation between ALDH1 expression with response to neoadjuvant therapy or overall survival after chemotherapy, in breast cancer patients (Resetkova et al, 2010).The clinical trials (phase I and II) in which CSCs were targeted with different mechanisms, have been summarized in Table 3.…”

“…To evaluate the prognostic impact and relevance of ALDH1 as a putative cancer stem cell marker in breast cancer (Resetkova et al, 2010) four cohorts series including an adjuvantly treated series of 245 invasive cancers, a neoadjuvantly treated series of 34 cases, and two series of 58 and 40 triple negative cases were studied by immunohistochemistry (IHC). In spite of prevoius studies that stated the role of CSCs in resistance to chemotherapies, this study showed that unexpected expression of ALDH1 in breast tumor cell did not correlate with response to neoadjuvant therapy, diseasefree or overall survival following adjuvant or neoadjuvant chemotherapy.…”

“…In spite of prevoius studies that stated the role of CSCs in resistance to chemotherapies, this study showed that unexpected expression of ALDH1 in breast tumor cell did not correlate with response to neoadjuvant therapy, diseasefree or overall survival following adjuvant or neoadjuvant chemotherapy. Therefore,based on Resetkova's study ALDH1 can not be suggested as a useful marker for targeted therapy of breast cancer (Resetkova et al, 2010).…”

High Expression of Stem Cell Marker ALDH1 is Associated with Reduced BRCA1 in Invasive Breast Carcinomas

“…CSC positive breast cancers, particularly ALDH1 positive cancers have been showed that to be more likely negative for ER and PR, but positive for HER2 and Ki67 correlating with more aggressive breast cancer subtypes (Morimoto et al, 2009;Zhou et al, 2010). Expression of ALDH1 was seen in stromal cells as well as epithelial cells of breast tumours which is associated with good outcome, concluding that tumour environment play a crucial role in determining the prognostic impact of stem cells Resetkova et al, 2010). Furthermore, it has been showed that knockdown of BRCA1 in primary breast epithelial cells leads to accumulation of cells expressing ALDH1 (Liu et al, 2008) In the present study, we evaluated both epithelial and stromal expression of ALDH1 to examine its relation with the clinicopathological characteristics of tumours in unselected series of breast carcinomas using immunohistochemistry.…”