The androgen receptor (AR) in syndromes of androgen insensitivity and in prostate cancer

Avila, D M; Zoppi, S.; McPhaul, Michael J.

doi:10.1016/s0960-0760(00)00158-8

Cited by 43 publications

(15 citation statements)

References 34 publications

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“…The fact that hormonal control of a tissue is lost upon progressive malignant transformation is not a new finding and besides loss of PR expression in endometrial cancer [20] this has also been described for other cancer types like breast cancer (loss of estrogen signaling [40]) and prostate cancer (loss of androgen signaling [41]) as well.…”

Section: Discussionmentioning

confidence: 90%

Progesterone Inhibits Epithelial-to-Mesenchymal Transition in Endometrial Cancer

Horst

Wang

Vandenput³

et al. 2012

PLoS ONE

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BackgroundEvery year approximately 74,000 women die of endometrial cancer, mainly due to recurrent or metastatic disease. The presence of tumor infiltrating lymphocytes (TILs) as well as progesterone receptor (PR) positivity has been correlated with improved prognosis. This study describes two mechanisms by which progesterone inhibits metastatic spread of endometrial cancer: by stimulating T-cell infiltration and by inhibiting epithelial-to-mesenchymal cell transition (EMT).Methodology and Principal FindingsParaffin sections from patients with (n = 9) or without (n = 9) progressive endometrial cancer (recurrent or metastatic disease) were assessed for the presence of CD4+ (helper), CD8+ (cytotoxic) and Foxp3+ (regulatory) T-lymphocytes and PR expression. Progressive disease was observed to be associated with significant loss of TILs and loss of PR expression. Frozen tumor samples, used for genome-wide expression analysis, showed significant regulation of pathways involved in immunesurveillance, EMT and metastasis. For a number of genes, such as CXCL14, DKK1, DKK4, PEG10 and WIF1, quantitive RT-PCR was performed to verify up- or downregulation in progressive disease. To corroborate the role of progesterone in regulating invasion, Ishikawa(IK) endometrial cancer cell lines stably transfected with PRA (IKPRA), PRB(IKPRB) and PRA+PRB (IKPRAB) were cultured in presence/absence of progesterone (MPA) and used for genome-wide expression analysis, Boyden- and wound healing migration assays, and IHC for known EMT markers. IKPRB and IKPRAB cell lines showed MPA induced inhibition of migration and loss of the mesenchymal marker vimentin at the invasive front of the wound healing assay. Furthermore, pathway analysis of significantly MPA regulated genes showed significant down regulation of important pathways involved in EMT, immunesuppression and metastasis: such as IL6-, TGF-β and Wnt/β-catenin signaling.ConclusionIntact progesterone signaling in non-progressive endometrial cancer seems to be an important factor stimulating immunosurveilance and inhibiting transition from an epithelial to a more mesenchymal, more invasive phenotype.

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Section: Discussionmentioning

confidence: 90%

Progesterone Inhibits Epithelial-to-Mesenchymal Transition in Endometrial Cancer

Horst

Wang

Vandenput³

et al. 2012

PLoS ONE

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“…The co-expression of estrogen receptor (ER) and AR in mammary epithelial cells suggests that the effects of estrogen and androgen on mammary epithelial proliferation are integrated within the mammary epithelial cell. The AR gene is located on the X chromosome with no corresponding allele on the Y, so it functions solely as a single copy gene, as shown by the complete loss of androgen effect in XY individuals with an inactivating mutation of the AR [14]. …”

Section: Androgen Receptormentioning

confidence: 99%

Androgens and the breast

2009

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Androgens have important physiological effects in women while at the same time they may be implicated in breast cancer pathologies. However, data on the effects of androgens on mammary epithelial proliferation and/or breast cancer incidence are not in full agreement. We performed a literature review evaluating current clinical, genetic and epidemiological data regarding the role of androgens in mammary growth and neoplasia. Epidemiological studies appear to have significant methodological limitations and thus provide inconclusive results. The study of molecular defects involving androgenic pathways in breast cancer is still in its infancy. Clinical and nonhuman primate studies suggest that androgens inhibit mammary epithelial proliferation and breast growth while conventional estrogen treatment suppresses endogenous androgens. Abundant clinical evidence suggests that androgens normally inhibit mammary epithelial proliferation and breast growth. Suppression of androgens using conventional estrogen treatment may thus enhance estrogenic breast stimulation and possibly breast cancer risk. Addition of testosterone to the usual hormone therapy regimen may diminish the estrogen/progestin increase in breast cancer risk but the impact of this combined use on mammary gland homeostasis still needs evaluation.

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“…The serine-rich region of DLC-3 also has potential motifs for binding to prolinerecognition domains, and thus this domain may possess multiple sites for interacting with other proteins to form signaling complexes. The gene-encoding DLC-3 is flanked by several wellcharacterized genes that are mutated in human genetic disorders, including androgen insensitivity (AR, Avila et al, 2001), one form of X-linked mental retardation (OPHN1, Billuart et al, 1998), and the skeletal disorder craniofrontonasal syndrome (EFNB1, Wieland et al, 2004). A female with craniofrontonasal syndrome was recently found to have a deletion of EFNB1 that also included part of STARD8/DLC3 (Twigg et al, 2006).…”

Section: -----------------------------------------------------------Dmentioning

confidence: 99%

Deleted in liver cancer 3 (DLC-3), a novel Rho GTPase-activating protein, is downregulated in cancer and inhibits tumor cell growth

et al. 2007

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The androgen receptor (AR) in syndromes of androgen insensitivity and in prostate cancer

Cited by 43 publications

References 34 publications

Progesterone Inhibits Epithelial-to-Mesenchymal Transition in Endometrial Cancer

Progesterone Inhibits Epithelial-to-Mesenchymal Transition in Endometrial Cancer

Androgens and the breast

Deleted in liver cancer 3 (DLC-3), a novel Rho GTPase-activating protein, is downregulated in cancer and inhibits tumor cell growth

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