132 research outputs found
Hormones and cancer: new insights, new challenges
No full textAbstract not availableWayne D. Tilley, Christine L. Clarke, Stephen N. Birrell and Nicholas Bruchovsk
Misdiagnosis of massive breast asymmetry: giant hamartoma
No full textAlexander L. Birrell, Leigh R. Warren and Stephen N. Birrel
Molecular and structural basis of androgen receptor responses to dihydrotestosterone, medroxyprogesterone acetate and Delta(4)-tibolone
No full textData source: Supplementary material, http://www.sciencedirect.com/science/article/pii/S0303720713004747#appd002Abstract not availableTina Bianco-Miotto, Andrew P. Trotta, Eleanor F. Need, Alice M.C. Lee, Aleksandra M. Ochnik,, Lauren Giorgio, Damien A. Leach, Erin E. Swinstead, Melissa A. O’Loughlin, Michelle R. Newman, Stephen N. Birrell, Lisa M. Butler, Jonathan M.Harris, Grant Buchana
Breast and prostate cancer: more similar than different
No full textBreast cancer and prostate cancer are the two most common invasive cancers in women and men, respectively. Although these cancers arise in organs that are different in terms of anatomy and physiological function both organs require gonadal steroids for their development, and tumours that arise from them are typically hormone-dependent and have remarkable underlying biological similarities. Many of the recent advances in understanding the pathophysiology of breast and prostate cancers have paved the way for new treatment strategies. In this Opinion article we discuss some key issues common to breast and prostate cancer and how new insights into these cancers could improve patient outcomes.Gail P. Risbridger, Ian D. Davis, Stephen N. Birrell and Wayne D. Tille
Disruption of androgen receptor signaling by synthetic progestins may increase risk of developing breast cancer
No full textCopyright © 2007 by The Federation of American Societies for Experimental BiologyThere is now considerable evidence that using a combination of synthetic progestins and estrogens in hormone replacement therapy (HRT) increases the risk of breast cancer compared with estrogen alone. Furthermore, the World Health Organization has recently cited combination contraceptives, which contain synthetic progestins, as potentially carcinogenic to humans, particularly for increased breast cancer risk. Given the above observations and the current trend toward progestin-only contraception, it is important that we have a comprehensive understanding of how progestins act in the millions of women worldwide who regularly take these medications. While synthetic progestins, such as medroxyprogesterone acetate (MPA), which are currently used in both HRT and oral contraceptives were designed to act exclusively through the progesterone receptor, it is clear from both clinical and experimental settings that their effects may be mediated, in part, by binding to the androgen receptor (AR). Disruption of androgen action by synthetic progestins may have serious deleterious side effects in the breast, where the balance between estrogen signaling and androgen signaling plays a critical role in breast homeostasis. Here, we review the role of androgen signaling in the normal breast and in breast cancer and present new data demonstrating that androgen receptor function can be perturbed by low doses of MPA, similar to doses achieved in serum of women taking HRT. We propose that the observed excess of breast malignancies associated with combined HRT may be explained, in part, by synthetic progestins such as MPA acting as endocrine disruptors to negate the protective effects of androgen signaling in the breast. Understanding the role of androgen signaling in the breast and how this is modulated by synthetic progestins is necessary to determine how combined HRT alters breast cancer risk, and to inform the development of optimal preventive and treatment strategies for this disease.Stephen N. Birrell, Lisa M. Butler, Jonathan M. Harris, Grant Buchanan and Wayne D. Tille
An androgen receptor mutation in the MDA-MB-453 cell line model of molecular apocrine breast cancer compromises receptor activity
No full textRecent evidence indicates that the estrogen receptor-α-negative, androgen receptor (AR)-positive molecular apocrine subtype of breast cancer is driven by AR signaling. The MDA-MB-453 cell line is the prototypical model of this breast cancer subtype; its proliferation is stimulated by androgens such as 5α-dihydrotestosterone (DHT) but inhibited by the progestin medroxyprogesterone acetate (MPA) via AR-mediated mechanisms. We report here that the AR gene in MDA-MB-453 cells contains a G-T transversion in exon 7, resulting in a receptor variant with a glutamine to histidine substitution at amino acid 865 (Q865H) in the ligand binding domain. Compared with wild-type AR, the Q865H variant exhibited reduced sensitivity to DHT and MPA in transactivation assays in MDA-MB-453 and PC-3 cells but did not respond to non-androgenic ligands or receptor antagonists. Ligand binding, molecular modeling, mammalian two-hybrid and immunoblot assays revealed effects of the Q865H mutation on ligand dissociation, AR intramolecular interactions, and receptor stability. Microarray expression profiling demonstrated that DHT and MPA regulate distinct transcriptional programs in MDA-MB-453 cells. Gene Set Enrichment Analysis revealed that DHT- but not MPA-regulated genes were associated with estrogen-responsive transcriptomes from MCF-7 cells and the Wnt signaling pathway. These findings suggest that the divergent proliferative responses of MDA-MB-453 cells to DHT and MPA result from the different genetic programs elicited by these two ligands through the AR-Q865H variant. This work highlights the necessity to characterize additional models of molecular apocrine breast cancer to determine the precise role of AR signaling in this breast cancer subtype.Nicole L Moore, Grant Buchanan, Jonathan M Harris, Luke A Selth, Tina Bianco-Miotto, Adrienne R Hanson, Stephen N Birrell, Lisa M Butler, Theresa E Hickey and Wayne D Tille
The magnitude of androgen receptor positivity in breast cancer is critical for reliable prediction of disease outcome
No full textPublished first March 7, 2018.Abstract not availableCarmela Ricciardelli, Tina Bianco-Miotto, Shalini Jindal, Lisa M. Butler, Samuel Leung, Catriona M. McNeil, Sandra A. O'Toole, Esmaeil Ebrahimie, Ewan K.A. Millar, Andrew J. Sakko, Alexandra I. Ruiz, Sarah L. Vowler, David G. Huntsman, Stephen N. Birrell, Robert L. Sutherland, Carlo Palmieri, Theresa E. Hickey, and Wayne D. Tille
Decreased androgen receptor levels and receptor function in breast cancer contribute to the failure of response to medroxyprogesterone acetate
No full textPreviously, we reported that androgen receptor (AR), but not estrogen receptor (ER) or progesterone receptor (PR), is predictive of response to the synthetic progestin, medroxyprogesterone acetate (MPA), in a cohort of 83 patients with metastatic breast cancer. To further investigate the role of AR in determining response to MPA in this cohort, we analyzed AR levels by immunohistochemistry with two discrete antisera directed at either the NH2 or the COOH termini of the receptor. Compared with tumors that responded to MPA (n = 31), there was a significant decrease in the intensity and extent of AR immunoreactivity with both AR antisera in tumors from nonresponders (n = 52). Whereas only a single AR immunostaining pattern was detected in responders to MPA, reflecting concordance of immunoreactivity with the two AR antisera, tumors from nonresponders exhibited four distinct AR immunostaining patterns: (a) concordance with the two antibodies (31%), (b) staining only with the COOH-terminal antibody (33%), (c) staining only with the NH2-terminal antibody (22%), or (d) no immunoreactivity with either NH2- or COOH-terminal antibody (14%). DNA sequencing and functional analysis identified inactivating missense gene mutations in the ligand-binding domain of the AR in tumors from two of nine nonresponders positive with the NH2-terminal AR antisera but negative for COOH-terminal immunoreactivity and lacking specific, high-affinity dihydrotestosterone binding in tumor cytosol fractions. Tumors with more AR than the median level (37 fmol/mg protein) had significantly lower levels of PR (30 fmol/mg protein) than tumors with low AR (PR; 127 fmol/mg protein) despite comparable levels of ER. Ligand-dependent activation of the AR in human T47D and MCF-7 breast cancer cells resulted in inhibition of estradiol-stimulated cell proliferation and a reduction in the capacity of the ER to induce expression of the PR. These effects could be reversed using a specific AR antisense oligonucleotide. Increasing the ratio of AR to ER resulted in a greater androgen-dependent inhibition of ER function. Collectively, these data suggest that reduced levels of AR or impaired AR function contribute to the failure of MPA therapy potentially due to abrogation of the inhibitory effect of AR on ER signaling.Grant Buchanan, Stephen N. Birrell, Amelia A. Peters, Tina Bianco-Miotto, Katrina Ramsay, Elisa J. Cops, Miao Yang, Jonathan M. Harris, Henry A. Simila, Nicole L. Moore, Jacqueline M. Bentel, Carmella Ricciardelli, David J. Horsfall, Lisa M. Butler and Wayne D. Tille
Androgen receptor inhibits estrogen receptor-alpha activity and is prognostic in breast cancer
No full text© 2009 American Association for Cancer ResearchThere is emerging evidence that the balance between estrogen receptor-alpha (ER(alpha)) and androgen receptor (AR) signaling is a critical determinant of growth in the normal and malignant breast. In this study, we assessed AR status in a cohort of 215 invasive ductal breast carcinomas. AR and (ER(alpha)) were coexpressed in the majority (80-90%) of breast tumor cells. Kaplan-Meier product limit analysis and multivariate Cox regression showed that AR is an independent prognostic factor in (ER(alpha))-positive disease, with a low level of AR (less than median of 75% positive cells) conferring a 4.6-fold increased risk of cancer-related death (P = 0.002). Consistent with a role for AR in breast cancer outcome, AR potently inhibited (ER(alpha))transactivation activity and 17beta-estradiol-stimulated growth of breast cancer cells. Transfection of MDA-MB-231 breast cancer cells with either functionally impaired AR variants or the DNA-binding domain of the AR indicated that the latter is both necessary and sufficient for inhibition of (ER(alpha)) signaling. Consistent with molecular modeling, electrophoretic mobility shift assays showed binding of the AR to an estrogen-responsive element (ERE). Evidence for a functional interaction of the AR with an ERE in vivo was provided by chromatin immunoprecipitation data, revealing recruitment of the AR to the progesterone receptor promoter in T-47D breast cancer cells. We conclude that, by binding to a subset of EREs, the AR can prevent activation of target genes that mediate the stimulatory effects of 17beta-estradiol on breast cancer cells.Amelia A. Peters, Grant Buchanan, Carmela Ricciardelli, Tina Bianco-Miotto, Margaret M. Centenera, Jonathan M. Harris, Shalini Jindal, Davendra Segara, Li Jia, Nicole L. Moore, Susan M. Henshall, Stephen N. Birrell, Gerhard A. Coetzee, Robert L. Sutherland, Lisa M. Butler and Wayne D. Tille
Antiproliferative actions of the synthetic androgen, mibolerone, in breast cancer cells are mediated by both androgen and progesterone receptors
No full textCopyright © 2008 Elsevier Ltd All rights reserved.Androgen signaling, mediated by the androgen receptor (AR), is a critical factor influencing growth of normal and malignant breast cells. Given the increasing use of exogenous androgens in women, a better understanding of androgen action in the breast is essential. This study compared the effects of 5alpha-dihydrotestosterone (DHT) and a synthetic androgen, mibolerone, on estradiol (E(2))-induced proliferation of breast cancer cells. DHT modestly inhibited E(2)-induced proliferation and mibolerone significantly inhibited proliferation in T-47D cells. The effects of both androgens could be reversed by an AR antagonist, suggesting that their actions were mediated, in part, by AR. Whereas high physiological doses (10-100nM) of DHT reduced E(2)-mediated induction of the estrogen-regulated gene progesterone receptor (PR) to basal levels, mibolerone at lower doses (1nM) eliminated PR expression, suggesting that mibolerone may also act via the PR. In the AR positive, PR-negative MCF-7 cells, mibolerone had modest effects on E(2)-induced proliferation, but was a potent inhibitor of proliferation in the AR positive, PR positive MCF-7M11 PRA cells. The effects of mibolerone in breast cancer cells were similar to those of the progestin, medroxyprogesterone acetate. Our results demonstrate that mibolerone can have both androgenic and progestagenic actions in breast cancer cells.Elisa J. Cops, Tina Bianco-Miotto, Nicole L. Moore, Christine L. Clarke, Stephen N. Birrell, Lisa M. Butler and Wayne D. Tilleyhttp://www.elsevier.com/wps/find/journaldescription.cws_home/333/description#descriptio
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