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Open Access 01-12-2016 | Research article

Alcohol-related breast cancer in postmenopausal women – effect of CYP19A1, PPARG and PPARGC1A polymorphisms on female sex-hormone levels and interaction with alcohol consumption and NSAID usage in a nested case-control study and a randomised controlled trial

Authors: Tine Iskov Kopp, Ditte Marie Jensen, Gitte Ravn-Haren, Arieh Cohen, Helle Molgaard Sommer, Lars Ove Dragsted, Anne Tjonneland, David Michael Hougaard, Ulla Vogel

Published in: BMC Cancer | Issue 1/2016

Abstract

Background

Alcohol consumption is associated with increased risk of breast cancer (BC), and the underlying mechanism is thought to be sex-hormone driven. In vitro and observational studies suggest a mechanism involving peroxisome proliferator-activated receptor gamma (PPARγ) in a complex with peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) and interaction with aromatase (encoded by CYP19A1). Use of non-steroidal anti-inflammatory drugs (NSAID) may also affect circulating sex-hormone levels by modifying PPARγ activity.

Methods

In the present study we assessed whether genetic variation in CYP19A1 is associated with risk of BC in a case-control study group nested within the Danish “Diet, Cancer and Health” cohort (n_cases = 687 and n_controls = 687) and searched for gene-gene interaction between CYP19A1 and PPARGC1A, and CYP19A1 and PPARG, and gene-alcohol and gene-NSAID interactions. Association between the CYP19A1 polymorphisms and hormone levels was also examined among 339 non-HRT users. Incidence rate ratios were calculated based on Cox’ proportional hazards model. Furthermore, we performed a pilot randomised controlled trial to determine the effect of the PPARG Pro¹²Ala polymorphism and the PPARγ stimulator Ibuprofen on sex-hormone levels following alcohol intake in postmenopausal women (n = 25) using linear regression.

Results

Genetic variations in CYP19A1 were associated with hormone levels (estrone: P_rs11070844 = 0.009, estrone sulphate: P_rs11070844 = 0.01, P_rs749292 = 0.004, P_rs1062033 = 0.007 and P_rs10519297 = 0.03, and sex hormone-binding globulin (SHBG): P_rs3751591 = 0.03) and interacted with alcohol intake in relation to hormone levels (estrone sulphate: P_{interaction/rs2008691} = 0.02 and P_{interaction/rs1062033=} 0.03, and SHBG: P_{interaction/rs11070844} = 0.03). CYP19A1/rs3751591 was both associated with SHBG levels (P = 0.03) and with risk of BC (Incidence Rate Ratio = 2.12; 95 % Confidence Interval: 1.02–4.43) such that homozygous variant allele carriers had increased levels of serum SHBG and were at increased risk of BC. Acute intake of alcohol decreased blood estrone (P = <0.0001), estrone sulphate (P = <0.0001), and SHBG (P = 0.009) levels, whereas Ibuprofen intake and PPARG Pro¹²Ala genotype had no effect on hormone levels.

Conclusions

Our results suggest that genetically determined variation in CYP19A1 is associated with differences in sex hormone levels. However, the genetically determined differences in sex hormone levels were not convincingly associated with BC risk. The results therefore indicate that the genetically determined variation in CYP19A1 contributes little to BC risk and to alcohol-mediated BC risk.

Trial registration

NCT02463383, June 3, 2015.

Available only for authorised users

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Title: Alcohol-related breast cancer in postmenopausal women – effect of CYP19A1, PPARG and PPARGC1A polymorphisms on female sex-hormone levels and interaction with alcohol consumption and NSAID usage in a nested case-control study and a randomised controlled trial
Authors: Tine Iskov Kopp
Ditte Marie Jensen
Gitte Ravn-Haren
Arieh Cohen
Helle Molgaard Sommer
Lars Ove Dragsted
Anne Tjonneland
David Michael Hougaard
Ulla Vogel
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2016
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-016-2317-y

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Pancreatic resection for intraductal papillary mucinous neoplasm– a thirteen-year single center experience

Antitumor effects of cecropin B-LHRH’ on drug-resistant ovarian and endometrial cancer cells

Keynote webinar | Spotlight on antibody–drug conjugates in cancer