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Steroid converting enzymes in breast cancer
Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Estrogens play a central role in the development of breast cancer. Most breast carcinomas are detected after menopause and despite a low degree of ovarian estrogen production and low levels of serum estrogen these tumors show a high in situ level of estrogens. Enzymes modulating local steroid availability seem to play an important role in the progression of especially estrogen receptor positive breast cancer. The 17ß-hydroxysteroid dehydrogenase (17ß-HSD) enzymes are involved in the interconversion of biologically active and inactive sex steroids and are considered to play a critical role in the in situ metabolism of estrogen.

The aim of this thesis was to investigate the expression of 17ß-HSD type 1 and 2 in breast cancer and correlate this to prognosis, and to analyze if the gene encoding 17ßHSD type 1 exhibits altered gene copy number in breast cancer. We also wanted to examine if the protein levels of aromatase, 17ßHSD type 1 and 17ßHSD type 2 show association with the expression of COX-2 in breast tumors and whether these proteins correlate to prognosis. Real-time RT-PCR was used to detect the rnRNA levels of 17ßHSD type 1 and type 2, and immunohistochemistry to detect the protein expression. To analyze if the gene encoding 17ßHSD type 1 exhibits altered gene copy number in breast cancer we used real-time PCR and genomic DNA.

While 17ßHSD type 1 catalyzes the conversion of estrone to the more potent estradiol, the type 2 enzyme catalyzes the opposite reaction. All tumors investigated in this study exhibited detectable rnRNA levels of 17ßHSD type 1. We found detectable rnRNA levels of 17ßHSD type 2 in the normal breast tissue, whereas many tumors lacked expression of type 2, especially among ER-positive tumors. In Paper I the expression of 17ßHSD type 2 was detectable in 14% of the tumors and in Paper III 17ßHSD type 2 mRNA was detected in 69% of the tumors. The expression of 17ßHSD type 2 seems to be lost in a subset of the breast tumors.

In Paper II we found amplification of the gene coding for 17ßHSD type 1 in 14.5% of the cases. HSD17B1 amplification had prognostic significance, and in particular, for ER-positive patients who received tamoxifen treatment, increased gene copy number indicated a decreased breast cancer survival. There was a significant correlation between HSD17B1 gene copy number and mRNA expression level of 17ßHSD type 1, when analyzing a subgroup of the patients.

In Paper II, among ER-positive patients, those with low expression of type 2 had a significantly higher recurrence rate compared with patients who expressed normal levels and this difference could not be seen among ER-negative patients. The prognostic significance of type 2 hold true in multivariate analysis. In Paper I, patients with late relapse in their disease more frequently had lost the mRNA expression of 17ßHSD type 2 than had matched control patients. In Paper IV, patients with ER-positive breast tumors with low protein levels of 17ßHSD type 2 had a worse prognosis, both concerning distant recurrence and breast cancer related death. In Paper I a high mRNA level of 17ßHSD type 1 predicted late relapses among breast cancer patients, however, in Paper IV a prognostic value of 17ßHSD type 1 could not be detected. In Paper III, there was no significant association between 17HSD type 1 and recurrence-free survival if the entire follow-up period was considered. However, for ER-positive patients still recurrence-free after 5 years, high levels of 17HSD type 1 was associated with a significantly higher rate of late relapse in the disease. When 17ßHSD type 1 and 2 were considered together, the expression ratio was a significant prognostic variable.

COX-2 protein expression was significantly correlated to aromatase, 17ßHSD type 1 and 17ßHSD type 2 levels, and this suggests that COX-2 might contribute to the upregulation of steroid converting enzymes. However, any significant prognostic value of COX-2 or aromatase could not be detected.

In summary, these results suggest that 17ß-HSD type 1 and 2 have prognostic importance in estrogen dependent breast cancer.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2005. , 76 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 908
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-31153Local ID: 16890ISBN: 91-85299-21-9 (print)OAI: oai:DiVA.org:liu-31153DiVA: diva2:251976
Public defence
2005-09-22, Berzeliussalen, Hälsouniversitetet, Linköping, 09:00 (Swedish)
Opponent
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-09-25Bibliographically approved
List of papers
1. Abnormal expression of 17β-hydroxysteroid dehydrogenases in breast cancer predicts late recurrence
Open this publication in new window or tab >>Abnormal expression of 17β-hydroxysteroid dehydrogenases in breast cancer predicts late recurrence
2001 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 61, no 23, 8448-8451 p.Article in journal (Refereed) Published
Abstract [en]

The 17β-hydroxysteroid dehydrogenase (17β-HSD) enzymes are involved in the interconversion of biologically active and inactive sex steroids and are considered to play a critical role in the in situ metabolism of estrogen, especially in estrogen-dependent breast cancer. The gene encoding 17β-HSD type 2 is located at 16q24.1-2, and earlier studies have shown that allelic loss in this region is an early and frequent event in breast cancer progression. Recurrence of hormone-dependent breast cancer frequently occurs several years after the primary treatment. The aim of this study was to investigate whether the expression of 17β-HSD types 1 and 2 differs in tumors from patients with late relapses (>5 years) compared with controls without recurrence after long-term follow-up. Using real-time reverse transcription-PCR, we found that the normal mammary gland expressed both 17β-HSD types 1 and 2, whereas the tumors frequently lacked detectable levels of type 2. Only 10% of the estrogen receptor-positive tumors expressed type 2, whereas 31% of the ERnegative tumors did so (P = 0.031). In a case-control series of 84 patients, a high level of 17β-HSD type 1 indicated increased risk to develop late relapse of breast cancer (odds ratio, 3.0; 95% confidence interval, 1.0–12.6; P = 0.041), whereas retained expression of type 2 indicated decreased risk (odds ratio, 0.25; 95% confidence interval, 0.05–1.2; P = 0.050). In multivariate analysis of the estrogen receptor-positive patients, the absence of 17β-HSD type 2 combined with a high expression of type 1 showed prognostic significance (P = 0.016) in addition to DNA aneuploidy (P = 0.0058), whereas progesterone receptor status did not (P = 0.71). These findings suggest that abnormal expression of 17β-HSD isoforms has prognostic significance in breast cancer and that altered expression of these enzymes may have importance in breast cancer progression.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24885 (URN)11731426 (PubMedID)9287 (Local ID)9287 (Archive number)9287 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
2. Amplification of HSD17B1 and ERBB2 in primary breast cancer
Open this publication in new window or tab >>Amplification of HSD17B1 and ERBB2 in primary breast cancer
Show others...
2003 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 22, no 1, 34-40 p.Article in journal (Refereed) Published
Abstract [en]

Estrogens play a crucial role in the development of breast cancer. Estradiol can be produced in the breast tissue in situ, and one of the enzymes involved in this process is 17β-hydroxysteriod dehydrogenase (17β-HSD) type 1 that catalyzes the interconversion of estrone (E1) to the biologically more potent estradiol (E2). The gene coding for 17β-HSD type 1 (HSD17B1) is located at 17q12-21, close to the more studied ERBB2 and BRCA1. The aim of this study was to investigate if HSD17B1 shows an altered gene copy number in breast cancer. We used real-time PCR and examined 221 postmenopausal breast tumors for amplification of HSD17B1 and ERBB2. In all, 32 tumors (14.5%) showed amplification of HSD17B1 and 21% were amplified for ERBB2. Amplification of the two genes was correlated (P = 0.00078) and in 14 tumors (44%) with amplification of HSD17B1, ERBB2 was co amplified. The patients with amplification in at least one of the genes had a significantly worse outcome than patients without (P = 0.0059). For estrogen receptor (ER)-positive patients who received adjuvant tamoxifen, amplification of HSD17B1 was related to decreased breast cancer survival (P = 0.017), whereas amplification of ERRB2 was not. Amplification of HSD17B1 might be an indicator of adverse prognosis among ER-positive patients, and possibly a mechanism for decreased benefit from tamoxifen treatment.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24842 (URN)10.1038/sj.onc.1206078 (DOI)12527905 (PubMedID)9240 (Local ID)9240 (Archive number)9240 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
3. 17β-hydroxysteroid dehydrogenases involved in local oestrogen synthesis have prognostic significance in breast cancer
Open this publication in new window or tab >>17β-hydroxysteroid dehydrogenases involved in local oestrogen synthesis have prognostic significance in breast cancer
2005 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 92, no 3, 547-552 p.Article in journal (Refereed) Published
Abstract [en]

The 17β-hydroxysteroid dehydrogenase (17HSD) enzymes are involved in the local regulation of sex steroids. The 17HSD type 1 enzyme catalyses the interconversion of the weak oestrone (E1) to the more potent oestradiol (E2), whereas 17HSD type 2 catalyses the oxidation of E2 to E1. The aim of this study was to correlate the expression of these enzymes in the tumour with the recurrence-free survival of tamoxifen-treated breast cancer patients. We used real-time reverse transcriptase PCR to investigate the mRNA expression of 17HSD types 1 and 2 in tumour samples from 230 postmenopausal patients. For the patients with oestrogen receptor (ER)-positive breast cancer, we found a statistically significant positive correlation between recurrence-free survival and expression of 17HSD type 2 (P = 0.026). We examined the ratio of 17HSD types 2 and 1, and ER-positive patients with low ratios showed a significantly higher rate of recurrence than those with higher ratios (P = 0.0047), ER positive patients with high expression levels of 17HSD type 1 had a significantly higher risk for late relapse (P = 0.0051). The expression of 17HSD types 1 and 2 in breast cancer differs from the expression of these enzymes in normal mammary gland, and this study indicates that the expression has prognostic significance in breast cancer.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24442 (URN)10.1038/sj.bjc.6602375 (DOI)6550 (Local ID)6550 (Archive number)6550 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
4. Expression of COX-2 and steroid converting enzymes in breast cancer
Open this publication in new window or tab >>Expression of COX-2 and steroid converting enzymes in breast cancer
Show others...
2006 (English)In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 16, no 2, 219-224 p.Article in journal (Refereed) Published
Abstract [en]

COX-2 is upregulated in many breast tumors, and one of the products of COX-2 is PGE2 that is suggested to upregulate aromatase through cAMP signaling in breast cancer. Although aromatase can increase the estrogen levels in tumors, 17β-hydroxysteroid dehydrogenase (17HSD) activity is finally needed for the estrone/estradiol regulation. The aim of this study was to investigate if the protein expression of enzymes involved in estrogen synthesis shows covariation with the expression of COX-2. We also wanted to correlate these results with prognosis. We analyzed the expression of COX-2, aromatase, 17HSD1 and 17HSD2 with immunohistochemistry using tissue microarrays composed of 356 primary breast tumors. In the present study COX-2 was correlated to aromatase (P<0.00001), 17HSD1 (P=0.0073), and 17HSD2 (P<0.00001). Patients with ER positive tumors expressing low amounts of 17HSD2 had decreased breast cancer survival (P=0.013). Elevated expression of COX-2 and aromatase was more frequent among larger tumors (P=0.017 and P=0.013). COX-2 expression correlates with the levels of the examined steroid converting enzymes and may contribute to increased estrogen levels in the tumor. In breast cancer cells, the regulatory function of 17HSD2 could be lost, and in the present study patients with low or non-detectable levels of 17HSD2 had worse prognosis than had breast cancer patients with higher levels of the enzyme.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-35971 (URN)16820896 (PubMedID)29152 (Local ID)29152 (Archive number)29152 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13Bibliographically approved

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