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Testosterone membrane-initiated action in breast cancer cells: Interaction with the androgen signaling pathway and EPOR.

ABSTRACT: Membrane-initiated androgen actions have now been acknowledged, even though a specific binding site has not been biochemically characterized yet. Recent data indicate that testosterone-BSA, a non-permeable testosterone analog, can exert specific actions in breast cancer cell lines, including proper transcriptional effects, independent of the intracellular androgen sites. In the present work we explore the effects of testosterone-BSA in two specifically modified pathways, revealed by early trascriptome analysis, namely the non-genotropic androgen signaling and the HIF1alpha pathway. We provide evidence that p38 MAPK and PI3K/Akt/NFkappaB and/or Rho/Actin pathways are directly involved in testosterone-induced apoptosis, while the JNK/c-JUN pathway is involved in membrane site-initiated transcription. Furthermore we show that membrane-acting androgens modify the transcription of the erythropoietin receptor (EPOR), leading to erythropoietin-initiated actions. Interestingly, association of recombinant human erythropoietin (rHuEPO) together with testosterone-BSA protects cells from apoptosis, through discrete signaling events. The effect of testosterone-BSA is exerted through the classical erythropoietin promoter, while rHuEPO decreases the transcription of EPOR acting on a newly identified regulatory/promoter region, upstream of its known promoter. These results suggest a new interaction of membrane-acting androgen with EPOR and should be taken into account in the pharmaceutical manipulations of breast cancer patients.

SUBMITTER: Pelekanou V

PROVIDER: S-EPMC5527892 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Testosterone membrane-initiated action in breast cancer cells: Interaction with the androgen signaling pathway and EPOR.

Pelekanou Vassiliki V Notas George G Sanidas Elias E Tsapis Andreas A Castanas Elias E Kampa Marilena M

Molecular oncology 20100202 2

Membrane-initiated androgen actions have now been acknowledged, even though a specific binding site has not been biochemically characterized yet. Recent data indicate that testosterone-BSA, a non-permeable testosterone analog, can exert specific actions in breast cancer cell lines, including proper transcriptional effects, independent of the intracellular androgen sites. In the present work we explore the effects of testosterone-BSA in two specifically modified pathways, revealed by early trascr ...[more]

PMID: 20189893

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Project description:BackgroundAndrogen receptors (AR) are frequently expressed in breast cancers, but their implication in cancer growth is still controversial. In the present study, we further investigated the role of the androgen/AR pathway in breast cancer development.MethodsAR expression was evaluated by immunochemistry in a cohort of 528 postmenopausal breast cancer patients previously examined for the association of serum testosterone levels with patient and tumor characteristics. AR expression was classified according to the percentage of stained cells: AR-absent (0%) and AR-poorly (1%-30%), AR-moderately (>30%-60%), and AR-highly (>60%) positive.ResultsStatistical analysis was performed in 451 patients who experienced natural menopause. AR-high expression was significantly related with low histologic grade and estrogen receptor (ER)- and progesterone receptor (PR)-positive status (P trend<0.001). Mean testosterone levels were significantly higher in the AR-high category than in the other categories combined (P=0.022), although a trend across the AR expression categories was not present. When women defined by ER status were analyzed separately, regression analysis in the ER-positive group showed a significant association of high testosterone levels with AR-highly-positive expression (OR 1.86; 95% CI, 1.10-3.16), but the association was essentially due to patients greater than or equal to 65 years (OR 2.42; 95% CI, 1.22-4.82). In ER-positive group, elevated testosterone levels appeared also associated with AR-absent expression, although the small number of patients in this category limited the appearance of significant effects (OR 1.92; 95% CI, 0.73-5.02): the association was present in both age groups (<65 and ≥65 years). In the ER-negative group, elevated testosterone levels were found associated (borderline significance) with AR-absent expression (OR 2.82, 95% CI, 0.98-8.06). In this ER-negative/AR-absent subset of tumors, elevated testosterone levels cannot stimulate cancer growth either directly or after conversion into estrogens, but they probably induce increased synthesis of some other substance that is responsible for cancer growth through binding to its specific receptor.ConclusionsThe findings in the present study confirm that testosterone levels are a marker of hormone-dependent breast cancer and suggest that the contemporary evaluation of ER status, AR expression, and circulating testosterone levels may identify different subsets of cancers whose growth may be influenced by androgens.

Dataset Information

Testosterone membrane-initiated action in breast cancer cells: Interaction with the androgen signaling pathway and EPOR.

Publications

Testosterone membrane-initiated action in breast cancer cells: Interaction with the androgen signaling pathway and EPOR.

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