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Int. J. Mol. Sci. 2017, 18(10), 2039; doi:10.3390/ijms18102039

Differential Functional Roles of ALDH1A1 and ALDH1A3 in Mediating Metastatic Behavior and Therapy Resistance of Human Breast Cancer Cells

1
London Regional Cancer Program, London Health Sciences Centre, 790 Commissioners Road East, London, ON N6A 4L6, Canada
2
Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 5C1, Canada
3
Department of Surgery, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 5C1, Canada
4
Department of Oncology, University of Alberta, 5-142C Katz Group Building, 114th St. and 87th Ave. S., Edmonton, AB T6G 2E1, Canada
5
Department of Oncology and Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 5C1, Canada
6
Cancer Research Laboratory Program, Lawson Health Research Institute, 750 Base Line Road, Suite 300, London, ON N6C 2R5, Canada
*
Author to whom correspondence should be addressed.
Received: 5 September 2017 / Revised: 18 September 2017 / Accepted: 18 September 2017 / Published: 22 September 2017
(This article belongs to the Special Issue Chemical and Molecular Approach to Tumor Metastases)
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Abstract

Previous studies indicate that breast cancer cells with high aldehyde dehydrogenase (ALDH) activity and CD44 expression (ALDHhiCD44+) contribute to metastasis and therapy resistance, and that ALDH1 correlates with poor outcome in breast cancer patients. The current study hypothesized that ALDH1 functionally contributes to breast cancer metastatic behavior and therapy resistance. Expression of ALDH1A1 or ALDH1A3 was knocked down in MDA-MB-468 and SUM159 human breast cancer cells using siRNA. Resulting impacts on ALDH activity (Aldefluor® assay); metastatic behavior and therapy response in vitro (proliferation/adhesion/migration/colony formation/chemotherapy and radiation) and extravasation/metastasis in vivo (chick choroiallantoic membrane assay) was assessed. Knockdown of ALDH1A3 but not ALDH1A1 in breast cancer cells decreased ALDH activity, and knockdown of ALDH1A1 reduced breast cancer cell metastatic behavior and therapy resistance relative to control (p < 0.05). In contrast, knockdown of ALDH1A3 did not alter proliferation, extravasation, or therapy resistance, but increased adhesion/migration and decreased colony formation/metastasis relative to control (p < 0.05). This is the first study to systematically examine the function of ALDH1 isozymes in individual breast cancer cell behaviors that contribute to metastasis. Our novel results indicate that ALDH1 mediates breast cancer metastatic behavior and therapy resistance, and that different enzyme isoforms within the ALDH1 family differentially impact these cell behaviors. View Full-Text
Keywords: breast cancer; metastasis; therapy resistance; ALDH1A1; ALDH1A3 breast cancer; metastasis; therapy resistance; ALDH1A1; ALDH1A3
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Croker, A.K.; Rodriguez-Torres, M.; Xia, Y.; Pardhan, S.; Leong, H.S.; Lewis, J.D.; Allan, A.L. Differential Functional Roles of ALDH1A1 and ALDH1A3 in Mediating Metastatic Behavior and Therapy Resistance of Human Breast Cancer Cells. Int. J. Mol. Sci. 2017, 18, 2039.

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