Aldehyde dehydrogenase 1A3 influences breast cancer progression via differential retinoic acid signaling

Abstract

Aldehyde dehydrogenase (ALDH) 1A enzymes produce retinoic acid (RA), a transcription induction molecule. To investigate if ALDH1A1 or ALDH1A3-mediated RA signaling has an active role in breast cancer tumorigenesis, we performed gene expression and tumor xenograft studies. Analysis of breast patient tumors revealed that high levels of ALDH1A3 correlated with expression of RA-inducible genes with retinoic acid response elements (RAREs), poorer patient survival and triple-negative breast cancers. This suggests a potential link between ALDH1A3 expression and RA signaling especially in aggressive and/or triple-negative breast cancers. In MDA-MB-231, MDA-MB-468 and MDA-MB-435 cells, ALDH1A3 and RA increased expression of RA-inducible genes. Interestingly, ALDH1A3 had opposing effects in tumor xenografts, increasing tumor growth and metastasis of MDA-MB-231 and MDA-MB-435 cells, but decreasing tumor growth of MDA-MB-468 cells. Exogenous RA replaced ALDH1A3 in inducing the same opposing tumor growth and metastasis effects, suggesting that ALDH1A3 mediates these effects by promoting RA signaling. Genome expression analysis revealed that ALDH1A3 induced largely divergent gene expression in MDA-MB-231 and MDA-MB-468 cells which likely resulted in the opposing tumor growth effects. Treatment with DNA methylation inhibitor 5-aza-2'deoxycytidine restored uniform RA-inducibility of RARE-containing HOXA1 and MUC4 in MDA-MB-231 and MDA-MB-468 cells, suggesting that differences in epigenetic modifications contribute to differential ALDH1A3/RA-induced gene expression in breast cancer. In summary, ALDH1A3 induces differential RA signaling in breast cancer cells which affects the rate of breast cancer progression.

ALDH1A3, the Major Aldehyde Dehydrogenase Isoform in Human Cholangiocarcinoma Cells, Affects Prognosis and Gemcitabine Resistance in Cholangiocarcinoma Patients

“…In addition, they also found that ALDH1B1 is dramatically upregulated in human colonic adenocarcinoma and therefore considering it as a potential biomarker for human colon cancer (23). Although high ALDH1A3 levels have already been detected in more aggressive forms of breast, bladder, and lung cancers (18,22,26), this work is nevertheless the first, to our knowledge, to report that ALDH1A3 is the main ALDH isoenzyme in intrahepatic cholangiocarcinoma. More importantly, we also found that ALDH1A3 is a critical prognostic factor in 77 patients with intrahepatic cholangiocarcinoma who received hepatectomies among several clinicopathologic features.…”

“…Elevated ALDH activity is also observed in leukemic SC populations in some acute myelogenous leukemia patients (13). ALDH1 serves as a marker of cancer SCs (CSC) in several types of solid tumors, including those of the liver (14), head and neck (15), pancreas (16), lung (17,18), prostate (19), bladder (20), ovary (21), breast (22), and colon (23). On the other hand, the potential of using increased ALDH activities to identify SC subpopulations in cholangiocarcinoma remains to be verified (24).…”

Implications of Different Cancer Stem Cell Phenotypes in Breast Cancer

“…Cells with a CSC phenotype characterized by ALDH activity were shown to have an improved ability for metastatic behavior in vitro (adhesion, colony formation, migration, and invasion) and metastases in vivo, supporting the hypothesis that CSCs might act as metastasis-initiating cells (14,49,(52)(53)(54).…”

“…Furthermore, increased expression of homeobox A1 and mucin 4 were associated with high ALDH1 activity, also contributing to tumor relapse and metastasis. Activation of transforming grow factor-beta 2 signaling pathway was also shown to be involved in the pathological regulation of ALDH1 in breast cancer (49)(50)(51).…”

The NAD+ salvage pathway modulates cancer cell viability via p73

“…RNA isolation from frozen human breast tumour samples, gene microarray analysis and data processing were as described previously. 39 The mRNA levels were estimated based on normalized gene microarray signal intensity. The cutoff values to define 'high' and 'low' levels for each gene were determined with receiver operating characteristic (ROC) curve analysis.…”