ALDH1A1 in breast cancer: A prospective target to overcome therapy resistance (Review)
Lokman Varisli1, Panagiotis Zoumpourlis2, Demetrios A Spandidos3
1Department of Molecular Biology and Genetics, Science Faculty, Dicle University, Diyarbakir 21280, Turkey.
Abstract:
The expression of cytosolic aldehyde dehydrogenases (ALDHs), which mediate the last step in the pathway of the synthesis of all-trans retinoic acid, is dysregulated in various types of human cancer, and has been associated with the development of cancer stem cells (CSCs) in solid tumors and hematological malignancies. CSCs are considered a minor fraction of cancer cells with the capacity to initiate neoplastic tumors. ALDH1A1 serves a crucial role in the emergence of the CSC phenotype, induces the malignant behavior of cancer cells and promotes treatment resistance. Notably, ALDH1A1-induced therapy resistance is not exclusive to just one group of drugs, but affects diverse types of drugs that use different mechanisms to kill cells. This diversity of drug resistance-inducing effects is associated with the stemness-supporting functions of ALDH1A1. The inhibition of ALDH1A1 activity using chemicals or the depletion of ALDH1A1 via genetic approaches, such as the use of small interfering RNA, can overcome diverse pathways of therapy resistance. In the context of breast cancer, it is critical that only a fraction of malignant cells are expected to manifest stem-like features, which include increased expression of ALDH1A1. From the angle of disease prognosis, the extent of the association of ALDH1A1 with increased malignant behavior and drug resistance remains to be determined through the application of cutting-edge methods that detect the expression of tracked biomarkers within tumors.
Insights
Cytosolic aldehyde dehydrogenases (ALDHs), particularly ALDH1A1, drive cancer stem cell (CSC) development and diverse drug resistance. Inhibiting ALDH1A1 shows promise in overcoming treatment resistance in various cancers.
Area of Science:
- Biochemistry
- Oncology
- Molecular Biology
Background:
- Cytosolic aldehyde dehydrogenases (ALDHs) are key in all-trans retinoic acid synthesis.
- ALDH dysregulation is linked to cancer stem cells (CSCs) in solid tumors and hematological malignancies.
- ALDH1A1 promotes CSC phenotype, malignancy, and broad drug resistance.
Purpose of the Study:
- To investigate the role of ALDH1A1 in cancer stem cell emergence and therapy resistance.
- To explore ALDH1A1's contribution to diverse drug resistance mechanisms.
- To assess the potential of ALDH1A1 inhibition for overcoming treatment resistance.
Main Methods:
- Analysis of ALDH expression in cancer cells.
- Investigating ALDH1A1's role in CSC phenotype and malignant behavior.
- Utilizing chemical inhibitors and genetic approaches (e.g., small interfering RNA) to target ALDH1A1.
- Examining ALDH1A1's impact on resistance to various drug classes.
Main Results:
- ALDH1A1 is crucial for CSC emergence and promotes malignant behavior.
- ALDH1A1 confers resistance to a wide range of drugs with different mechanisms.
- Inhibition of ALDH1A1 activity or expression effectively overcomes diverse therapy resistance pathways.
- Increased ALDH1A1 expression is associated with stem-like features in breast cancer cells.
Conclusions:
- ALDH1A1 is a significant driver of cancer stemness and multifaceted drug resistance.
- Targeting ALDH1A1 presents a viable strategy to enhance cancer therapy efficacy.
- Further research using advanced biomarker detection methods is needed to clarify ALDH1A1's prognostic value in various cancers.
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