Androgens Act Synergistically to Enhance Estrogen-induced Upregulation of Human Tissue Kallikreins 10, 11, and 14 in Breast Cancer Cells Via a Membrane Bound Androgen Receptor

Overview

Journal Mol Oncol

Specialties Molecular Biology
Oncology

Date 2009 Apr 23

PMID 19383315

Citations 10

Authors

Miltiadis Paliouras

Eleftherios P Diamandis

Affiliations

Soon will be listed here.

Abstract

The regulation of gene expression by steroid hormones plays an important role in the normal development and function of many organs, as well as in the pathogenesis of endocrine-related cancers, especially breast cancer. However, clinical data suggest that combined testosterone and estrogen treatments on post-menopausal women increase the risk of breast cancer. Experiments have shown that many, if not all kallikreins are under steroid hormone regulation in breast cancer cell lines. Their implication as prognostic and diagnostic markers has also been well-documented. Thus, we investigated the effect of combined hormone stimulation with androgens and 17beta-estradiol on the ductal caricinoma cell line BT474. This cell line has been shown to be sensitive to both, androgens (secreting PSA) and estrogens (secreting a number of kallikreins including KLK10, 11, and KLK14). We found that PSA expression was downregulated upon combined hormone stimulation, confirming reports that estrogen can antagonize and block the activity of the androgen receptor. Upon analysis of estrogen-sensitive kallikreins 10, 11, and 14, all showed to be synergistically enhanced in their expression three- to fourfold, upon joint hormone treatment versus individual hormone stimulation. The enhancement is dependent upon the action of androgens as treatment with the androgen receptor antagonist cyproterone actetate normalized the expression of KLK10, 11, and KLK14 to estrogen-stimulation levels. The synergistic effects between estrogens and androgens on estrogen-sensitive genes may have implications on the role of the kallikreins in associated risk of breast cancer and progression.

Citing Articles

Could Kallikrein-Related Serine Peptidase 3 Be an Early Biomarker of Environmental Exposure in Young Women?.

Raimondo S, Gentile M, Esposito G, Gentile T, Ferrara I, Crescenzo C Int J Environ Res Public Health. 2021; 18(16).

PMID: 34444582 PMC: 8392638. DOI: 10.3390/ijerph18168833.

Estrogen receptor-α prevents right ventricular diastolic dysfunction and fibrosis in female rats.

Cheng T, Philip J, Tabima D, Kumari S, Yakubov B, Frump A Am J Physiol Heart Circ Physiol. 2020; 319(6):H1459-H1473.

PMID: 33064565 PMC: 7792707. DOI: 10.1152/ajpheart.00247.2020.

Post-menopausal breast cancer: from estrogen to androgen receptor.

Majumder A, Singh M, Tyagi S Oncotarget. 2017; 8(60):102739-102758.

PMID: 29254284 PMC: 5731994. DOI: 10.18632/oncotarget.22156.

Genome-wide association studies and genomic prediction of breeding values for calving performance and body conformation traits in Holstein cattle.

Abo-Ismail M, Brito L, Miller S, Sargolzaei M, Grossi D, Moore S Genet Sel Evol. 2017; 49(1):82.

PMID: 29115939 PMC: 6389134. DOI: 10.1186/s12711-017-0356-8.

Steroid hormone receptors as prognostic markers in breast cancer.

Louie M, Sevigny M Am J Cancer Res. 2017; 7(8):1617-1636.

PMID: 28861319 PMC: 5574935.

References

Kaaks R, Rinaldi S, Key T, Berrino F, Peeters P, Biessy C . Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition. Endocr Relat Cancer. 2005; 12(4):1071-82. DOI: 10.1677/erc.1.01038. View

Stathopoulos E, Dambaki C, Kampa M, Theodoropoulos P, Anezinis P, Delakas D . Membrane androgen binding sites are preferentially expressed in human prostate carcinoma cells. BMC Clin Pathol. 2003; 3:1. PMC: 149438. DOI: 10.1186/1472-6890-3-1. View

Perel E, Wilkins D, Killinger D . The conversion of androstenedione to estrone, estradiol, and testosterone in breast tissue. J Steroid Biochem. 1980; 13(1):89-94. DOI: 10.1016/0022-4731(80)90117-x. View

Walker G, Macleod K, Williams A, Cameron D, Smyth J, Langdon S . Insulin-like growth factor binding proteins IGFBP3, IGFBP4, and IGFBP5 predict endocrine responsiveness in patients with ovarian cancer. Clin Cancer Res. 2007; 13(5):1438-44. DOI: 10.1158/1078-0432.CCR-06-2245. View

McCubrey J, Steelman L, Abrams S, Lee J, Chang F, Bertrand F . Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul. 2006; 46:249-79. DOI: 10.1016/j.advenzreg.2006.01.004. View

Maggiolini M, Donze O, Jeannin E, Ando S, Picard D . Adrenal androgens stimulate the proliferation of breast cancer cells as direct activators of estrogen receptor alpha. Cancer Res. 1999; 59(19):4864-9. View

Pampalakis G, Sotiropoulou G . Multiple mechanisms underlie the aberrant expression of the human kallikrein 6 gene in breast cancer. Biol Chem. 2006; 387(6):773-82. DOI: 10.1515/BC.2006.097. View

Yousef G, Diamandis E . Human tissue kallikreins: a new enzymatic cascade pathway?. Biol Chem. 2002; 383(7-8):1045-57. DOI: 10.1515/BC.2002.113. View

Somboonporn W, Davis S . Postmenopausal testosterone therapy and breast cancer risk. Maturitas. 2004; 49(4):267-75. DOI: 10.1016/j.maturitas.2004.06.020. View

10.

Sidiropoulos M, Pampalakis G, Sotiropoulou G, Katsaros D, Diamandis E . Downregulation of human kallikrein 10 (KLK10/NES1) by CpG island hypermethylation in breast, ovarian and prostate cancers. Tumour Biol. 2005; 26(6):324-36. DOI: 10.1159/000089290. View

11.

Cleutjens K, van der Korput H, van Eekelen C, van Rooij H, Faber P, Trapman J . An androgen response element in a far upstream enhancer region is essential for high, androgen-regulated activity of the prostate-specific antigen promoter. Mol Endocrinol. 1997; 11(2):148-61. DOI: 10.1210/mend.11.2.9883. View

12.

Zhou J, Ng S, Anderson K, Bondy C . Testosterone inhibits estrogen-induced mammary epithelial proliferation and suppresses estrogen receptor expression. FASEB J. 2000; 14(12):1725-30. DOI: 10.1096/fj.99-0863com. View

13.

Paliouras M, Diamandis E . The kallikrein world: an update on the human tissue kallikreins. Biol Chem. 2006; 387(6):643-52. DOI: 10.1515/BC.2006.083. View

14.

Lacroix M, Leclercq G . Relevance of breast cancer cell lines as models for breast tumours: an update. Breast Cancer Res Treat. 2004; 83(3):249-89. DOI: 10.1023/B:BREA.0000014042.54925.cc. View

15.

Luo L, Grass L, Diamandis E . Steroid hormone regulation of the human kallikrein 10 (KLK10) gene in cancer cell lines and functional characterization of the KLK10 gene promoter. Clin Chim Acta. 2003; 337(1-2):115-26. DOI: 10.1016/j.cccn.2003.07.008. View

16.

Vilgelm A, Lian Z, Wang H, Beauparlant S, Klein-Szanto A, Ellenson L . Akt-mediated phosphorylation and activation of estrogen receptor alpha is required for endometrial neoplastic transformation in Pten+/- mice. Cancer Res. 2006; 66(7):3375-80. DOI: 10.1158/0008-5472.CAN-05-4019. View

17.

Obiezu C, Diamandis E . Human tissue kallikrein gene family: applications in cancer. Cancer Lett. 2005; 224(1):1-22. DOI: 10.1016/j.canlet.2004.09.024. View

18.

Stein R, McDonnell D . Estrogen-related receptor alpha as a therapeutic target in cancer. Endocr Relat Cancer. 2007; 13 Suppl 1:S25-32. DOI: 10.1677/erc.1.01292. View

19.

Recanatini M, Bisi A, Cavalli A, Belluti F, Gobbi S, Rampa A . A new class of nonsteroidal aromatase inhibitors: design and synthesis of chromone and xanthone derivatives and inhibition of the P450 enzymes aromatase and 17 alpha-hydroxylase/C17,20-lyase. J Med Chem. 2001; 44(5):672-80. DOI: 10.1021/jm000955s. View

20.

Magklara A, Grass L, Diamandis E . Differential steroid hormone regulation of human glandular kallikrein (hK2) and prostate-specific antigen (PSA) in breast cancer cell lines. Breast Cancer Res Treat. 2000; 59(3):263-70. DOI: 10.1023/a:1006304518750. View