ERα/LKB1 complex upregulates E-cadherin expression and stimulates breast cancer growth and progression upon adiponectin exposure |
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Authors: | Giuseppina Daniela Naimo Martina Forestiero Alessandro Paolì Rocco Malivindi Luca Gelsomino Balázs Gy?rffy Adele Elisabetta Leonetti Francesca Giordano Salvatore Panza Francesca Luisa Conforti Paola Ruffo Maria Luisa Panno Loredana Mauro Sebastiano Andò |
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Institution: | 1. Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy;2. Department of Bioinformatics, Semmelweis University, Budapest, Hungary
Cancer Biomarker Research Group, Research Centre for Natural Sciences, Budapest, Hungary;3. Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
Medical Genetics Laboratory, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy |
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Abstract: | Adiponectin is the major adipocytes-secreted protein involved in obesity-related breast cancer growth and progression. We proved that adiponectin promotes proliferation in ERα-positive breast cancer cells, through ERα transactivation and the recruitment of LKB1 as ERα-coactivator. Here, we showed that adiponectin-mediated ERα transactivation enhances E-cadherin expression. Thus, we investigated the molecular mechanism through which ERα/LKB1 complex may modulate the expression of E-cadherin, influencing tumor growth, progression and distant metastasis. We demonstrated that adiponectin increases E-cadherin expression in ERα-positive 2D and higher extent in 3D cultures. This occurs through a direct activation of E-cadherin gene promoter by ERα/LKB1-complex. The impact of E-cadherin on ERα-positive breast cancer cell proliferation comes from the evidence that in the presence of E-cadherin siRNA the proliferative effects of adiponectin is no longer noticeable. Since E-cadherin connects cell polarity and growth, we investigated if the adiponectin-enhanced E-cadherin expression could influence the localization of proteins cooperating in cell polarity, such as LKB1 and Cdc42. Surprisingly, immunofluorescence showed that, in adiponectin-treated MCF-7 cells, LKB1 and Cdc42 mostly colocalize in the nucleus, impairing their cytosolic cooperation in maintaining cell polarity. The orthotopic implantation of MCF-7 cells revealed an enhanced E-cadherin-mediated breast cancer growth induced by adiponectin. Moreover, tail vein injection of MCF-7 cells showed a higher metastatic burden in the lungs of mice receiving adiponectin-treated cells compared to control. From these findings it emerges that adiponectin treatment enhances E-cadherin expression, alters cell polarity and stimulates ERα-positive breast cancer cell growth in vitro and in vivo, sustaining higher distant metastatic burden. |
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Keywords: | adiponectin breast cancer E-cadherin estrogen receptor alpha (ERα) LKB1 |
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