Increased aldehyde dehydrogenase 1 (ALDH1) levels are associated with chemo-responsiveness in breast cancer patients treated with taxane–adriamycin–cyclophosphamide regimen

BACKGROUND: Increased plasma aldehyde dehydrogenase 1 (ALDH1) levels have been proposed to predict cancer chemoresistance. However, studies have reported inconsistent results, depending on the type of cancer cells used. OBJECTIVE: This study aimed to investigate the correlation between plasma levels of ALDH1 and chemotherapy responses to the taxane–adriamycin–cyclophosphamide (TAC) regimen in breast cancer patients. METHODS: Thirty breast cancer patients who underwent chemotherapy using the TAC regimen were included in this study. Blood sampling was performed before chemotherapy was initiated and after the first and third cycles of chemotherapy administration. After 3 cycles of chemotherapy, patients were categorized as non-responsive if the tumor size was reduced <30%, if the tumor size remained the same or increased, or if any new tumors were discovered. Patients were defined as responsive after 3 cycles of chemotherapy if the tumor mass disappeared, if the tumor size was reduced by at least 30% of the initial size and if no new tumors were found. RESULTS: Among the 30 patients, only five were responsive to the TAC regimen. The clinical response to TAC was not correlated with the patient’s age, cancer grading, or tumor stage. A change in the ALDH1 levels was observed after the third cycle of TAC administration, with significantly higher ALDH1 levels observed in responsive compared with non-responsive patients (p < 0.05). CONCLUSION: The results of this study may indicate a role for ALDH1 in chemoresponsiveness, rather than chemoresistance, for the TAC regimen in breast cancer patients. Further research remains necessary to confirm this result.

Differential expression of aldehyde dehydrogenase 1 family member A1 in cancers of the breast.

Breast cancer affects women at relatively high frequency (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding aldehyde dehydrogenase 1 family member A1, ALDH1A1, when comparing primary tumors of the breast to the tissue of origin, the normal breast. ALDH1A1 mRNA was present at significantly lower quantities in tumors of the breast as compared to normal breast tissue. Analysis of human survival data revealed that expression of ALDH1A1 in primary tumors of the breast was correlated with overall survival in patients with luminal A subtype cancer, demonstrating a relationship between primary tumor expression of a differentially expressed gene and patient survival outcomes influenced by molecular subtype. ALDH1A1 may be of relevance to initiation, maintenance or progression of cancers of the female breast.

Differential expression of aldehyde dehydrogenase 1 family member A2 in cancers of the breast.

Breast cancer affects women at relatively high frequency (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding aldehyde dehydrogenase 1 family member A2, ALDH1A2, when comparing primary tumors of the breast to the tissue of origin, the normal breast. ALDH1A2 mRNA was present at significantly lower quantities in tumors of the breast as compared to normal breast tissue. Analysis of human survival data revealed that expression of ALDH1A2 in primary tumors of the breast was correlated with overall survival in patients with luminal A subtype and HER2+ cancer, but in a contrary manner, demonstrating a complex relationship between primary tumor expression of a differentially expressed gene and patient survival outcomes influenced by molecular subtype. ALDH1A2 may be of relevance to initiation, maintenance or progression of cancers of the female breast.

Aldehyde Dehydrogenase 1 Isoforms ALDH1A1 and ALDH1A3 are Essential for Myogenic Differentiation

Background Satellite cells (SC) constitute the stem cell population of skeletal muscle tissue and are determinants for myogenesis. Aldehyde Dehydrogenase 1 (ALDH1) enzymatic activity correlates with myogenic properties of SCs and, recently, we could show co-localization of its isoforms ALDH1A1 and ALDH1A3 in SCs of human skeletal muscle. ALDH1 is not only the pacemaker enzyme in retinoic acid signaling and differentiation, but also protecting cell maintenance against oxidative stress products. However, the molecular mechanism of ALDH1 in SC activation and regulation of myogenesis has not yet been characterized. In regard of ALDH1A1 and ALDH1A1 expression in myogenesis human RH30 and murine C2C12 myoblast cell lines were investigated using Western Blot, Immunofluorescence and Aldefluor Assay. Results Here, we show, that isoforms ALDH1A1 and ALDH1A3 are pivotal factors in the process of myogenic differentiation, since ALDH1A1 knock-out and ALDH1A3 knock-out, respectively, impaired differentiation potential. Recombinant re-expression of ALDH1A1 and ALDH1A3, respectively, in corresponding ALDH1-isoform knock-out cells recovered their differentiation potential. Most interestingly, the chemical inhibition of enzymatic activity by disulfiram leads to ALDH1A1 and ALDH1A3 protein upregulation and subsequent myogenic differentiation. Conclusion Our findings indicate that ALDH1A1 and ALDH1A3 proteins are important for myogenic differentiation and, therefore, seem to be essential activators and regulators of SCs.

Aldehyde Dehydrogenase 1 isoforms ALDH1A1 and ALDH1A3 are essential for myogenic differentiation

Background Satellite cells (SC) constitute the stem cell population of skeletal muscle tissue and are determinants for myogenesis. Aldehyde Dehydrogenase 1 (ALDH1) enzymatic activity correlates with myogenic properties of SCs and, recently, we could show co-localization of its isoforms ALDH1A1 and ALDH1A3 in SCs of human skeletal muscle. ALDH1 is not only the pacemaker enzyme in retinoic acid signaling and differentiation, but also protecting cell maintenance against oxidative stress products. However, the molecular mechanism of ALDH1 in SC activation and regulation of myogenesis has not yet been characterized. Method Human RH30 and murine C2C12 myoblast cell lines were investigated in regard of ALDH1A1 and ALDH1A1 expression in myogenesis using Western Blot, Immunofluorescence and Aldefluor Assay. Results Here, we show, that isoforms ALDH1A1 and ALDH1A3 are pivotal factors in the process of myogenic differentiation, since ALDH1A1 knock-out and ALDH1A3 knock-out, respectively, impaired differentiation potential. Recombinant re-expression of ALDH1A1 and ALDH1A3, respectively, in corresponding ALDH1-isoform knock-out cells recovered their differentiation potential. Most interestingly, the chemical inhibition of enzymatic activity by disulfiram leads to ALDH1A1 and ALDH1A3 protein upregulation and subsequent myogenic differentiation. Conclusion Our findings indicate that ALDH1A1 and ALDH1A3 proteins are important for myogenic differentiation and, therefore, seem to be essential activators and regulators of SCs.