The role of aromatase and 17-Î²-hydroxysteroid dehydrogenase type 1 mRNA expression in predicting the clinical outcome of human breast cancer

Salhab, Mohamed; Reed, Michael J.; Sarakbi, W Al; Jiang, Wen Guo; Mokbel, Kefah

doi:10.1007/s10549-006-9198-8

Cited by 34 publications

(16 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Because increased aromatase activity results from increased aromatase gene expression, (25,26) we next evaluated the effect of AIs on the levels of mRNA aromatase (CYP19) expression. Formestane alone markedly reduced CYP19 expression (50-60%); the inhibition was greater in the presence of herceptin (85-90%) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Combined inhibitory effect of formestane and herceptin on a subpopulation of CD44+/CD24low breast cancer cells

Cavaliere¹,

Corvigno²,

Galgani³

et al. 2010

Cancer Science

View full text Add to dashboard Cite

In breast cancer, stromal cells surrounding cancer epithelial cells can influence phenotype by producing paracrine factors. Among many mediators of epithelial-stromal interactions, aromatase activity is perhaps one of the best studied. Clinical data suggest that estrogen-independent signaling leads to increased proliferation even during therapy with aromatase inhibitors (AIs). Molecular mechanism of crosstalk between the estrogen receptor (ER) and the epidermal growth factor receptor (HER) family have been implicated in resistance to endocrine therapy, but this interaction is unclear. The ability of aromatase to induce estradiol biosynthesis provides a molecular rationale to combine agents that target aromatase activity and the HER pathway. We targeted stromal-epithelial interactions using formestane, which exerts antiaromatase activity, combined with the monoclonal anti-HER2 antibody herceptin, in a subpopulation of CD44+/CD24low cells sorted from epithelial-mesenchymal co-cultures of breast cancer tissues. The growth inhibition was respectively 16% (P < 0.01) in the response to herceptin, 25% to formestane (P < 0.01), and 50% (P < 0.001) with the combination of the two drugs, suggesting that herceptin cooperates with formestane-induced inhibition of aromatase and this effect could be mediated through HER family receptors. In cells which expressed ERa, formestane/herceptin combination suppressed the mRNA expression of aromatase and HER2 and decreased cyclin D1 expression. These results show that combination therapies involving AIs and anti-HER2 can be efficacious for the treatment of cancer in experimental models and suggest that subtyping breast tumors gives useful information about response to treatment. (Cancer Sci 2010; 101: 1661-1669 T umor phenotype is influenced by genetic and epigenetic alterations, tumor stroma, and the systemic environment, which lead to a complex mixture of factors that represent the tumor microenvironment.(1) Estrogens play a critical role in the development of breast cancer. Six enzymes catalyze the conversion of cholesterol to biologically active 17-b-estradiol (E2). The aromatase enzyme catalyzes the final and key step of estrogen biosynthesis, that is the conversion of C19 steroids to estrogens. In premenopausal women, most plasma estrogen is synthesized in the ovaries and a small proportion (<10%) derives from peripheral synthesis by aromatase, which is present in subcutaneous fat. As a woman ages, the breast's epithelial tissue is gradually replaced by adipocytes. In postmenopausal women, estrogens are synthesized by peripheral aromatization from androgens and peripheral aromatase activity increases with age.(2) Most patients with breast cancer are postmenopausal women and 75% of them have estrogen-dependent tumors defined by estrogen receptor (ER) positivity.(3,4) As estrogens synthesized locally or peripherally by aromatase are able to induce mitogenic signals, the ER has long represented the target for endocrine therapies that aim to block the action of estrogen on tumor ce...

show abstract

Section: Resultsmentioning

confidence: 99%

Combined inhibitory effect of formestane and herceptin on a subpopulation of CD44+/CD24low breast cancer cells

Cavaliere¹,

Corvigno²,

Galgani³

et al. 2010

Cancer Science

View full text Add to dashboard Cite

show abstract

“…17 β HSD1 and 17 β HSD2 are involved in the interconversion of E2 with the less potent E1 [33]. Increased 17 β HSD1 expression in breast cancer, either alone or in combination with CYP19, enhances estrogen concentrations and negatively impacts prognosis [50, 51], as does loss of 17 β HSD2 expression [52]. In the present study, the mRNA expression of pro-estrogenic 17 β HSD1 was detected in MCF10A cells but was more abundant in the neoplastic MCF10CA1a and MCF10DCIS.com variants.…”

Section: Discussionmentioning

confidence: 99%

Expression of estrogenicity genes in a lineage cell culture model of human breast cancer progression

Weise

Falany

et al. 2009

Breast Cancer Res Treat

View full text Add to dashboard Cite

TaqMan Gene Expression assays were used to profile the mRNA expression of estrogen receptor (ERα and ERβ) and estrogen metabolism enzymes including cytosolic sulfotransferases (SULT1E1, SULT1A1, SULT2A1, and SULT2B1), steroid sulfatase (STS), aromatase (CYP19), 17β-hydroxysteroid dehydrogenases (17βHSD1 and 2), CYP1B1, and catechol-O-methyltransferase (COMT) in an MCF10A-derived lineage cell culture model for basal-like human breast cancer progression and in ERα-positive luminal MCF7 breast cancer cells. Low levels of ERα and ERβ mRNA were present in MCF10A-derived cell lines. SULT1E1 mRNA was more abundant in confluent relative to subconfluent MCF10A cells, a non-tumorigenic proliferative breast disease cell line. SULT1E1 was also expressed in preneoplastic MCF10AT1 and MCF10AT1K.cl2 cells, but was markedly repressed in neoplastic MCF10A-derived cell lines as well as in MCF7 cells. Steroid-metabolizing enzymes SULT1A1 and SULT2B1 were only expressed in MCF7 cells. STS and COMT were widely detected across cell lines. Pro-estrogenic 17βHSD1 mRNA was most abundant in neoplastic MCF10CA1a and MCF10DCIS.com cells, while 17βHSD2 mRNA was more prominent in parental MCF10A cells. CYP1B1 mRNA was most abundant in MCF7 cells. Treatment with the histone deacetylase inhibitor trichostatin A (TSA) induced SULT1E1 and CYP19 mRNA but suppressed CYP1B1, STS, COMT, 17βHSD1, and 17βHSD2 mRNA in MCF10A lineage cell lines. In MCF7 cells, TSA treatment suppressed ERα, CYP1B1, STS, COMT, SULT1A1, and SULT2B1 but induced ERβ, CYP19 and SULT2A1 mRNA expression. The results indicate that relative to the MCF7 breast cancer cell line, key determinants of breast estrogen metabolism are differentially regulated in the MCF10A-derived lineage model for breast cancer progression.

show abstract

“…This results in an increased level of E 2 that drives the proliferation of the tumour tissue via the ER. Several studies have indicated that patients with tumours that have high 17b-HSD1 expression have significantly shortened disease-free and overall survival (Gunnarsson et al 2005, Salhab et al 2006, Vihko et al 2006, suggesting that compounds which inhibit the activity of this enzyme may be of therapeutic benefit in the treatment of hormone-dependent breast cancer in post-menopausal patients .…”

Section: B-hsd1 Inhibitionmentioning

confidence: 99%

Design and validation of specific inhibitors of 17 -hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis

Day¹,

Tutill²,

Purohit³

et al. 2008

Endocrine Related Cancer

115

View full text Add to dashboard Cite

Abstract17b-Hydroxysteroid dehydrogenases (17b-HSDs) are enzymes that are responsible for reduction or oxidation of hormones, fatty acids and bile acids in vivo, regulating the amount of the active form that is available to bind to its cognate receptor. All require NAD(P)(H) for activity. Fifteen 17b-HSDs have been identified to date, and with one exception, 17b-HSD type 5 (17b-HSD5), an aldo-keto reductase, they are all short-chain dehydrogenases/reductases, although overall homology between the enzymes is low. Although named as 17b-HSDs, reflecting the major redox activity at the 17b-position of the steroid, the activities of these 15 enzymes vary, with several of the 17b-HSDs able to reduce and/or oxidise multiple substrates at various positions. These activities are involved in the progression of a number of diseases, including those related to steroid metabolism. Despite the success of inhibitors of steroidogenic enzymes in the clinic, such as those of aromatase and steroid sulphatase, the development of inhibitors of 17b-HSDs is at a relatively early stage, as at present none have yet reached clinical trials. However, many groups are now working on inhibitors specific for several of these enzymes for the treatment of steroid-dependent diseases, including breast and prostate cancer, and endometriosis, with demonstrable efficacy in in vivo disease models. In this review, the recent advances in the validation of these enzymes as targets for the treatment of these diseases, with emphasis on 17b-HSD1, 3 and 5, the development of specific inhibitors, the models used for their evaluation, and their progress towards the clinic will be discussed.

show abstract

The role of aromatase and 17-Î²-hydroxysteroid dehydrogenase type 1 mRNA expression in predicting the clinical outcome of human breast cancer

Abstract: Our study shows that higher levels of the enzymes responsible for the local biosynthesis of estrogens especially aromatase are associated with a poor clinical outcome in patients with breast cancer.

Cited by 34 publications

References 55 publications

Combined inhibitory effect of formestane and herceptin on a subpopulation of CD44+/CD24low breast cancer cells

Combined inhibitory effect of formestane and herceptin on a subpopulation of CD44+/CD24low breast cancer cells

Expression of estrogenicity genes in a lineage cell culture model of human breast cancer progression

Design and validation of specific inhibitors of 17 -hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis

Contact Info

Product

Resources

About