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Role of ALDH1A1 and HTRA2 expression in CCL2/CCR2-mediated breast cancer cell growth and invasion
Hu, Qingting Myers, Megan Fang, Wei Yao, Min Brummer, Gage Hawj, Justin Smart, Curtis Berkland, Cory Cheng, Nikki
Hu, Qingting
Myers, Megan
Fang, Wei
Yao, Min
Brummer, Gage
Hawj, Justin
Smart, Curtis
Berkland, Cory
Cheng, Nikki
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Abstract
Chemokines mediate immune cell trafficking during tissue development, wound healing and infection. The chemokine CCL2 is best known to regulate macrophage recruitment during wound healing, infection and inflammatory diseases. While the importance of CCL2/CCR2 signaling in macrophages during cancer progression is well documented, we recently showed that CCL2-mediated breast cancer progression depends on CCR2 expression in carcinoma cells. Using 3D Matrigel: Collagen cultures of SUM225 and DCIS.com breast cancer cells, this study characterized the mechanisms of CCL2/CCR2 signaling in cell growth and invasion. SUM225 cells, which expressed lower levels of CCR2 than DCIS.com cells, formed symmetrical spheroids in Matrigel: Collagen, and were not responsive to CCL2 treatment. DCIS.com cells formed asymmetric cell clusters in Matrigel: Collagen. CCL2 treatment increased growth, decreased expression of E-cadherin and increased TWIST1 expression. CCR2 overexpression in SUM225 cells increased responsiveness to CCL2 treatment, enhancing growth and invasion. These phenotypes corresponded to increased expression of Aldehyde Dehydrogenase 1A1 (ALDH1A1) and decreased expression of the mitochondrial serine protease HTRA2. CCR2 deficiency in DCIS.com cells inhibited CCL2-mediated growth and invasion, corresponding to decreased ALDH1A1 expression and increased HTRA2 expression. ALDH1A1 and HTRA2 expression were modulated in CCR2-deficient and CCR2-overexpressing cell lines. We found that ALDH1A1 and HTRA2 regulates CCR2-mediated breast cancer cell growth and cellular invasion in a CCL2/CCR2 context-dependent manner. These data provide novel insight on the mechanisms of chemokine signaling in breast cancer cell growth and invasion, with important implications on targeted therapeutics for anti-cancer treatment.
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This work is licensed under a Creative Commons Attribution 4.0 International License.
Date
2019-06-28
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Publisher
The Company of Biologists
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Keywords
CCL2, CCR2, Breast cancer, 3D culture, Cell invasion, ALDH1A1, HTRA2
Citation
Qingting Hu, Megan Myers, Wei Fang, Min Yao, Gage Brummer, Justin Hawj, Curtis Smart, Cory Berkland, Nikki Cheng, "Role of ALDH1A1 and HTRA2 expression in CCL2/CCR2-mediated breast cancer cell growth and invasion", Biology Open 2019 8: bio040873 doi: 10.1242/bio.040873 Published 28 June 2019