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Functional analysis of the -2548G/A leptin gene polymorphism in breast cancer cells

✍ Scribed by Marianna Terrasi; Elena Fiorio; Anna Mercanti; Mariusz Koda; Camilo A. Moncada; Stanislaw Sulkowski; Salim Merali; Antonio Russo; Eva Surmacz

Publisher
John Wiley and Sons
Year
2009
Tongue
French
Weight
242 KB
Volume
125
Category
Article
ISSN
0020-7136

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✦ Synopsis

Abstract

Leptin is overexpressed in human breast tumors and is produced by breast cancer cells in response to obesity‐related stimuli. The leptin promoter polymorphism Lep‐2548G/A can be associated with increased leptin secretion by adipocytes and elevated cancer risk. However, molecular mechanisms underlying the link between Lep‐2548G/A and breast cancer have never been addressed. Lep‐2548G/A is proximal to a binding site for the transcriptional factor Sp1. Furthermore nucleolin, a transcriptional repressor, can bind Sp1 or its consensus site. Consequently, we focused on the impact of Lep‐2548G/A on Sp1‐ and nucleolin‐dependent leptin transcription in breast cancer cells. The Lep‐2548G/A was identified in a homozygous conformation in BT‐474 and SK‐BR‐3 breast cancer cells, in a heterozygous conformation in MDA‐MB‐231 cells, and a wild‐type Lep‐2548G/G sequence was present in MCF‐7 and ZR‐75‐1 cells. The occurrence of Lep‐2548A/A and Lep‐2548G/A coincided with high and intermediate leptin mRNA expression, respectively, while cells containing Lep‐2548G/G expressed low leptin mRNA levels. We demonstrated that the existence of Lep‐2548G/A improved efficient recruitment of Sp1 to DNA under insulin treatment, while Sp1 loading on DNA containing Lep‐2548G/G was not insulin‐dependent. In contrast, nucleolin binding to Lep‐2548G/A was downregulated in response to insulin, while it was not regulated on Lep‐2548G/G. The presence of Lep‐2548G/A was studied in breast cancer epithelial cells by IHC and LCM. Interestingly, all 14 tumors expressing high leptin levels contained Lep‐2548A/A. In conclusion, the occurrence of Lep‐2548G/A can enhance leptin expression in breast cancer cells via Sp1‐ and nucleolin‐dependent mechanisms and possibly contribute to intratumoral leptin overexpression. © 2009 UICC

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