London Regional Cancer Program, London Health Sciences Centre, 790 Commissioners Road East, London, ON N6A 4L6, Canada.
Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 5C1, Canada.
Int J Mol Sci. 2017 Sep 22;18(10):2039. doi: 10.3390/ijms18102039.
Previous studies indicate that breast cancer cells with high aldehyde dehydrogenase (ALDH) activity and CD44 expression (ALDHCD44⁺) 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 ( < 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 ( < 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.
先前的研究表明，具有高醛脱氢酶（ALDH）活性和 CD44 表达（ALDHCD44+）的乳腺癌细胞有助于转移和治疗耐药性，并且 ALDH1 与乳腺癌患者的不良预后相关。本研究假设 ALDH1 可在功能上促进乳腺癌转移行为和治疗耐药性。使用 siRNA 敲低 MDA-MB-468 和 SUM159 人乳腺癌细胞中的 ALDH1A1 或 ALDH1A3 表达。评估对 ALDH 活性（Aldefluor 测定）；体外转移行为和治疗反应（增殖/粘附/迁移/集落形成/化疗和放疗）以及体内渗出/转移（鸡胚绒毛尿囊膜试验）的影响。与对照相比，乳腺癌细胞中 ALDH1A3 的敲低而非 ALDH1A1 的敲低降低了 ALDH 活性，并且 ALDH1A1 的敲低降低了乳腺癌细胞的转移行为和治疗耐药性（<0.05）。相比之下，ALDH1A3 的敲低并未改变增殖、渗出或治疗耐药性，但与对照相比，增加了粘附/迁移，减少了集落形成/转移（<0.05）。这是第一项系统研究 ALDH1 同工酶在促进转移的个别乳腺癌细胞行为中的功能的研究。我们的新结果表明，ALDH1 介导乳腺癌转移行为和治疗耐药性，并且 ALDH1 家族中的不同酶同工酶对这些细胞行为有不同的影响。
