PubMed Health⌕ Search

Biomedical subjects

Anthony P Heaney

Publications and source records attributed to Anthony P Heaney.

14 recordsLinked to original sources
PubMed2013

Evidence for orphan nuclear receptor TR4 in the etiology of Cushing disease.

Cushing disease (CD) is a life-threatening disorder attributed to excess pituitary tumor-derived adrenocorticotrophic hormone (ACTH) and adrenal steroid secretion caused by pituitary tumors. Whereas CD was first described in 1932, the underlying genetic basis driving tumor growth and ACTH secretion remains unsolved. Here, we show that testicular orphan nuclear receptor 4 (TR4, nuclear receptor subfamily 2, group C, member 2) is overexpressed in human corticotroph tumors as well as in human and mouse corticotroph tumor cell lines. Forced overexpression of TR4 in both human and murine tumor cells increased proopiomelanocortin transcription, ACTH secretion, cellular proliferation, and tumor invasion rates in vitro. Conversely, knockdown of TR4 expression reversed all phenotypes. Mechanistically, we show that TR4 transcriptionally activates proopiomelanocortin through binding of a direct repeat 1 response element in the promoter, and that this is enhanced by MAPK-mediated TR4 phosphorylation. In vivo, TR4 overexpression promotes murine corticotroph tumor growth as well as enhances ACTH and corticosterone production, whereas TR4 knockdown decreases circulating ACTH and corticosterone levels in mice harboring ACTH-secreting tumors. Our findings directly link TR4 to the etiology of corticotroph tumors, hormone secretion, and cell growth as well as identify it as a potential target in the treatment of CD.

ACTH-Secreting Pituitary Adenoma↗
PubMed2006

Pituitary tumour pathogenesis.

Pituitary adenomas are the most common tumours in the central nervous system, make up approximately 10% of all primary intracerebral tumours [1] and are found incidentally in 3-27% of autopsies [2]. The predisposition to tumour formation of the highly specialized cellular phenotypes that characterize the anterior pituitary is unexplained, but it is tempting to speculate that the same hormones, growth factors and cytokines derived from intra- and extra-pituitary sites that maintain tight hypothalamic pituitary control may also contribute to pituicyte transformation. The interplay between genetic and humoural factors to promote cellular transformation is exemplified in pituitary tumorigenesis and is discussed in this review.

Adenoma↗
PubMed2005

Alpha1-adrenergic receptor antagonists: novel therapy for pituitary adenomas.

Pituitary tumors are common and cause considerable morbidity due to local invasion and altered hormone secretion. Doxazosin (dox), a selective alpha(1)-adrenergic receptor antagonist, used to treat hypertension, also inhibits prostate cancer cell proliferation. We examined the effects of dox on murine and human pituitary tumor cell proliferation in vitro and in vivo. dox treatment inhibited proliferation of murine pituitary tumor cells, induced G(0)-G(1) cell cycle arrest, and reduced phosphorylated retinoblastoma levels. In addition, increased annexin-fluorescein isothiocyanate immunoreactivity and cleaved caspase-3 levels, in keeping with dox-mediated apoptosis, were observed in the human and murine pituitary tumor cells, and dox administration to mice, harboring corticotroph tumors, decreased tumor growth and reduced plasma ACTH levels. dox-mediated antiproliferative and proapoptotic actions were not confined to alpha-adrenergic receptor-expressing pituitary tumor cells and were unaffected by cotreatment with the alpha-adrenergic receptor blocker, phenoxybenzamine. dox treatment led to reduced phosphorylated inhibitory kappaB (IkappaB)-alpha expression, and nuclear factor-kappaB transcription and decreased basal and TNFalpha-induced proopiomelanocortin transcriptional activation. These results demonstrate that the selective alpha(1)-adrenergic receptor antagonist dox inhibits pituitary tumor cell growth in vitro and in vivo by mechanisms that are in part independent of its alpha-adrenergic receptor-blocking actions and involve down-regulation of nuclear factor-kappaB signaling. dox is proposed as a possible novel medical therapy for pituitary tumors.

ACTH-Secreting Pituitary Adenoma↗
PubMed2005

Securin is overexpressed in breast cancer.

Securin regulates sister chromatid separation during mitosis, induces bFGF-mediated angiogenesis, and securin overexpression causes in vitro transformation and in vivo tumor formation in nude mice. As estrogen administration to oophorectomized rats increased pituitary securin expression, we used immunohistochemistry to examine securin and estrogen receptor alpha (ER-alpha) expression in 90 breast tumors and 18 normal breast tissues. Breast tumor securin and ER-alpha expression were quantitated by image analysis and expressed as fold difference relative to securin expression in normal breast tissue. Low cytoplasmic securin expression was seen in the normal breast epithelium, whereas abundant cytoplasmic and nuclear securin expression was demonstrated in all 90 breast tumors. Highest securin expression was seen in brain metastatic breast tumors (4.3-fold, P<0.01), cells derived from metastatic breast cancers (6.5-fold, P<0.001), and in invasive ductal carcinoma (mean+/-s.e.: 3.8-fold, P<0.001). Highly pleomorphic (4.1-fold) or highly proliferative breast tumors (1.6-fold) exhibited high immunohistochemical securin expression compared to low-grade breast tumors (P<0.05). Northern blot analysis in 12 of the breast tumors confirmed the immunohistochemical findings demonstrating increased securin mRNA expression compared to normal breast mucosa (2.5-fold, P=0.03), with highest securin evident in invasive (3.5-fold) vs noninvasive tumors (1.9-fold, P=0.03). In addition, some tumors that exhibited high securin expression also expressed high ER-alpha levels (P<0.0001). These results demonstrate that the estrogen-induced transforming gene, securin is abundantly expressed in breast carcinoma, and is associated with the presence of metastatic spread, and lymph node invasion. We propose immunohistochemical tumor securin expression as a potential invasive marker, and novel therapeutic target in breast cancer.

Analysis of Variance↗
PubMed2004

PPAR-gamma in Cushing's disease.

The majority of pituitary tumors that cause Cushing's disease are small (<1 cm diameter), and most disease morbidity is due to the effects of elevated, non-suppressible, ACTH levels that these tumors secrete. Tumor-derived ACTH leads to adrenal-derived steroid hypersecretion and results in many disabling and sometimes life-threatening symptoms including abnormal fat deposition, skin thinning, psychological disturbances, hypertension, diabetes, osteoporosis and muscle weakness. Cushing's disease is associated with high morbidity and ultimately mortality. In experienced specialized centers, 70% of corticotroph microadenomas can be successfully resected by transsphenoidal pituitary surgery. However, surgical "cure" rates for larger ACTH-secreting pituitary tumors are achieved in only 30% of cases, and recent reports highlight a significant recurrence rate after longer term follow-up even in smaller tumors. Post-surgical persistence of ACTH hypersecretion may require pituitary-directed radiation, but this treatment may take some time to be effective, and like extensive surgical pituitary tumor resection, ultimately leads to partial- or total hypopituitarism in approximately 80% of cases. Although hypercortisolism may be completely resolved by adrenalectomy, this procedure does not suppress, and may act as a stimulus to pituitary tumor growth, and is associated with other co-morbidity. Although some currently available drug-based treatments for Cushing's disease effectively control hypercortisolism, their drawback has been that they do not impact on pituitary tumor growth. Recent studies have identified the potential utility of peroxisome-proliferator activating receptor-gamma (PPAR-gamma) novel ligands in in vitro, and in vivo Cushing's disease models, and have paved the way for early clinical studies to develop novel therapeutic approaches in Cushing's disease.

ACTH-Secreting Pituitary Adenoma↗
PubMed2003

Human pituitary tumor-transforming gene (PTTG1) motif suppresses prolactin expression.

Pituitary tumor-transforming gene (PTTG) originally isolated from GH-secreting pituitary adenoma cells causes in vitro cell transformation, in vivo tumorigenesis, and induces basic fibroblast growth factor. These functions require an intact C-terminal proline-proline-serine-proline motif. PTTG1 is abundantly expressed in human pituitary tumors and plays a role in the early stages of experimental prolactinoma formation. We now determined direct effects of PTTG1 on hormonal phenotypes of functional pituitary tumor cells. Overexpression of PTTG1 C terminus (amino acids 147-202) containing intact proline-proline-serine-proline motifs in rat prolactin (PRL)- and GH-secreting GH3 cells markedly abrogates PRL mRNA expression by more than 90% (P < 0.001) and hormone levels (P < 0.001) and PRL promoter activity (P < 0.01) compared with control vector cells or to a PTTG1 C terminus mutant (P163A, S165Q, P166L, P170L, P172A, and P173L). Wild-type PTTG1 C-terminal transfectants formed smaller (P < 0.05) sc tumors in rats compared with control or mutated PTTG1 C-terminal transfectants. Estrogen (10 nm) treatment for 48 h partially restored PRL expression in stable wild-type PTTG1 C-terminal transfectants. These results indicate that targeting PTTG1-mediated signaling alters the hormonal phenotype in pituitary cells and disrupted PTTG1 action may be a potential subcellular therapeutic tool for repressing PRL hypersecretion.

Amino Acid Motifs↗
PubMed2003

Novel pituitary ligands: peroxisome proliferator activating receptor-gamma.

Pituitary tumors cause considerable morbidity due to local invasion, hypopituitarism, or hormone hypersecretion. In many cases, no suitable drug therapies are available, and surgical excision is currently the only effective treatment. We have recently demonstrated abundant expression of nuclear hormone receptor PPAR-gamma in human pituitary tumors of different subtypes. PPAR-gamma activators (thiazolidinediones) induced G0-G1 cell-cycle arrest and apoptosis in human, and murine corticotroph, somatolactotroph, and gonadotroph pituitary tumor cells, and suppressed in vitro hormone secretion. In vivo development and growth of murine corticotroph, somatolactotroph and gonadotroph tumors, generated by subcutaneous injection of ACTH-secreting AtT20, PRL- and GH-secreting GH3, and LH-secreting LbetaT2, and alpha-T3 cells, was markedly suppressed in rosiglitazone treated mice, and plasma ACTH, and serum corticosterone, GH, PRL and LH levels were attenuated in all treated animals. PPAR-gamma is an important novel molecular target in pituitary adenoma cells and as PPAR-gamma ligands inhibit tumor cell growth and ACTH, GH, PRL and LH secretion in vitro and in vivo, thiazolidinediones are proposed as a novel oral medical management for pituitary tumors.

Adrenocorticotropic Hormone↗
PubMed2003

PPAR-gamma receptor ligands: novel therapy for pituitary adenomas.

Pituitary tumors cause considerable morbidity due to local invasion, hypopituitarism, or hormone hypersecretion. In many cases, no suitable drug therapies are available, and surgical excision is currently the only effective treatment. We show here abundant expression of nuclear hormone receptor PPAR-gamma in all of 39 human pituitary tumors. PPAR-gamma activating thiazolidinediones (TZDs) rosiglitazone and troglitazone induced G(0)-G(1) cell-cycle arrest and apoptosis in human, rat somatolactotroph, and murine gonadotroph pituitary tumor cells, and suppressed in vitro hormone secretion. In vivo development and growth of murine somatolactotroph and gonadotroph tumors, generated by subcutaneous injection of prolactin-secreting (PRL-secreting) and growth hormone-secreting (GH-secreting) GH3 cells, luteinizing hormone-secreting (LH-secreting) LbetaT2 cells, and alpha-T3 cells, was markedly suppressed in rosiglitazone-treated mice, and serum GH, PRL, and LH levels were attenuated in all treated animals (P < 0.009). These results demonstrate that PPAR-gamma is an important molecular target in pituitary adenoma cells and PPAR-gamma ligands inhibit tumor cell growth and GH, PRL, and LH secretion in vitro and in vivo. TZDs are proposed as novel oral medications for managing pituitary tumors.

Adenoma↗
PubMed2003

Leukemia inhibitory factor regulates prolactin secretion in prolactinoma and lactotroph cells.

Leukemia inhibitory factor (LIF) stimulates the hypothalamic-pituitary-adrenal axis, and transgenic mice overexpressing pituitary LIF develop Cushing-like syndrome accompanied by reduced prolactin (PRL) expression. Effects of LIF were, therefore, tested on PRL expression in human prolactinomas and normal and tumorous rat lactotrophs. Normal human pituitary tissue expressed LIF, as well as the LIF receptor (LIFR) signaling subunits, gp130 and LIFR. Although all of 19 prolactinomas tested expressed gp130 and LIFR subunit mRNA and immunoreactive protein, only 3 of 19 prolactinomas expressed LIF mRNA. All of four prolactinomas had no detectable LIF immunoreactivity, in contrast to all other pituitary tumor types that expressed LIF. LIF (5 nM) treatment reduced PRL secretion in primary human prolactinoma cultures by up to 42% (P < 0.0005), an effect that was surprisingly blocked by sulpiride, a D2-like dopamine receptor antagonist. LIF (5 nM) also suppressed PRL levels in primary rat pituitary cultures by 70% (P < 0.005), and in rat MMQ pituitary tumor cells, and this effect was also reversed by sulpiride (200 micro M). D2R agonist suppression of PRL was not additive with LIF. GH levels in these cells were unchanged by LIF, consistent with a selective effect on PRL. Transfection of human long-form D2R into an LIF-resistant MMQ cell clone restored LIF responsiveness. These results show that even though human prolactinomas express gp130 and LIFR, and respond to exogenous LIF, albeit less than normal lactotrophs, they are largely devoid of LIF. These observations indicate a role for LIF in loss of autocrine PRL suppression contributing to unrestrained prolactinomas PRL secretion. Moreover, PRL suppression by LIF may be mediated by gp130 and D2R interaction.

Adenoma↗
PubMed2002

Functional PPAR-gamma receptor is a novel therapeutic target for ACTH-secreting pituitary adenomas.

Adrenocorticotrophic hormone (ACTH)-secreting pituitary tumors are associated with high morbidity due to excess glucocorticoid production. No suitable drug therapies are currently available, and surgical excision is not invariably curative. Here we demonstrate immunoreactive expression of the nuclear hormone receptor peroxisome proliferator-activated receptor-gamma (PPAR-gamma) exclusively in normal ACTH-secreting human anterior pituitary cells: PPAR-gamma was abundantly expressed in all of six human ACTH-secreting pituitary tumors studied. PPAR-gamma activators induced G0/G1 cell-cycle arrest and apoptosis and suppressed ACTH secretion in human and murine corticotroph tumor cells. Development of murine corticotroph tumors, generated by subcutaneous injection of ACTH-secreting AtT20 cells, was prevented in four of five mice treated with the thiazolidinedione compound rosiglitazone, and ACTH and corticosterone secretion was suppressed in all treated mice. Based on these findings, thiazolidinediones may be an effective therapy for Cushing disease

Adrenal Glands↗
PubMed2002

Functional role of estrogen in pituitary tumor pathogenesis.

Pituitary hyperplasia and lactotroph replication are induced by estrogen. The product of the pituitary tumor transforming gene (PTTG) exhibits in vitro and in vivo transforming activity and induces basic bFGF secretion, thereby modulating pituitary angiogenesis and tumor formation. We demonstrated previously that pituitary pttg is induced by estrogen and bFGF, the latter being expressed in a concordant fashion with pttg in experimental and human pituitary adenomas. We now elucidate the role of estrogen in paracrine regulation of pituitary tumorigenesis by PTTG. Coincident with the circulating rat estradiol surge and maximal pituitary proliferation, pituitary pttg mRNA, bFGF, and VEGF expression increased approximately threefold during proestrus and estrus. Osmotic mini-pump coinfusion of estrogen and antiestrogen abrogated estrogen-induced pituitary pttg expression in vivo, suppressed serum PRL concentrations by 88%, and attenuated prolactin-secreting pituitary tumor growth by 41% in rats. Antiestrogen treatment of primary human pituitary tumor cultures reduced PTTG expression approximately 65%. Pituitary pttg, bFGF, and VEGF are cyclically expressed during the rat estrus cycle, concordantly with estrogen levels. Because anti-estrogens reduced PTTG expression in human pituitary tumors in vitro and suppressed experimental tumor growth in vivo, concomitantly with reduced PRL secretion, these results indicate a role for selective antiestrogens in treating pituitary tumors.

Adenoma↗