Abstract 355: Genetic alterations in 17β-hydroxysteroid dehydrogenase type 2 and 7 correlates with mRNA-expression but not estrogen levels in breast cancer

Abstract

Abstract Background: Estrogens are believed to play an important role in both development and sustained growth of breast cancer. Estradiol (E2), the most biologically active estrogen, is often elevated in breast cancer tissue, and high plasma levels of E2 are correlated to increased breast cancer risk in postmenopausal women. Previously, we have shown that uptake of estrogen due to binding to the estrogen receptor (ER), is a probable determinant of intratumoral E2. Furthermore, we reported that increased expression of 17β-hydroxysteroid dehydrogenase type 7 (HSD17B7) might explain the increased ratio of E2 to estrone (E1) in breast tumors compared to non-tumorous breast tissue. Here we explored whether genetic alterations in HSD17B-isoforms might predict estrogen disposition in breast cancer. Materials and methods: Tumor and normal breast tissue specimens were collected from 50 patients (37 postmenopausal and 13 premenopausal women) undergoing mastectomy. Samples were snap-frozen in the theatre. To evaluate potential mechanisms regulating intra-tumor and plasma estradiol levels, HSD17B2 and HSD17B7 were evaluated for mutation status, promoter hypermethylation and gene copy number. In addition, we quantified the transcription level of two HSD17B7 isoforms (HSD17B7_I and HSD17B7_II). Results: We identified a novel single nucleotide polymorphism (SNP) in the HSD17B7 promoter region (transcription start + 56: T>C) and found it correlated to increased enzyme expression level (p = 0.016). Also, we observed a novel SNP in the HSD17B2 promoter region (transcription start + 35: C>T) associated with a lower expression level (p = 0.019). Nineteen patients were found to harbour HSD17B7-duplications predicting elevated mRNA-expression levels (p = 0.056). While some tumors revealed promoter hypermethylation in both HSD17B2 and 7, hypermethylation status was not associated with low mRNA-levels. None of these genetic alterations correlated to plasma or tissue estrogen levels. Conclusion: Genetic alterations in HSD17B2 and 7 were found to influence the transcription level of these genes, but not estradiol levels in plasma or breast cancer tissue. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 355. doi:10.1158/1538-7445.AM2011-355