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Biomedical subjects

N J Kenney

Publications and source records attributed to N J Kenney.

At least 19 recordsLinked to original sources
PubMed1996

Detection of amphiregulin and Cripto-1 in mammary tumors from transgenic mice.

Epidermal growth factor family members are widely expressed in human breast cancer and are thought to play an important dual role in mammary gland development and tumorigenesis. Overexpression of two relatively new members of this family, amphiregulin (AR) and Cripto-1 (CR-1), has been previously shown to transform immortalized human and mouse mammary epithelial cells. Here, we extend these results and address the disregulated expression of AR and CR-1 in many types of transgenic neoplastic mouse mammary tissues. Transgenic mouse strains overexpressing the oncogenes transforming growth factor-alpha, neu, int-3, polyoma virus middle T antigen, and simian virus 40 large T antigen have been previously shown to develop spontaneous mammary neoplasia. These models were each examined for mammary-tumor expression of AR and CR-1 by reverse transcription-polymerase chain reaction, western blot, and immunocytochemical analyses. Mammary tumors from each source expressed AR and CR-1. Western blot analysis revealed that, in all mammary tumors, AR and CR-1 protein species were processed differently than in virgin and lactating mouse mammary tissue. In addition, immunohistochemical detection of AR and CR-1 in tumor tissue revealed different patterns of growth-factor localization in different types of transgenic mouse mammary-derived tumors. These findings are consistent with the possibility of widespread roles for AR and CR-1 in the promotion and/or progression stages of mouse mammary tumorigenesis.

Amphiregulin↗
PubMed1996

Growth factor and sex steroid interactions in breast cancer.

Mitogenic and inhibitory growth factors and steroid ovarian hormones play important roles as selective modulators of normal mammary development and in the onset and the progression of human breast cancer. The focus of this article is to review past and current research on the interactions of these two classes of effectors in mammary gland development and neoplasia. Steroid hormones regulate synthesis of growth stimulatory and inhibitory growth factors, growth factor receptors, and growth factor binding proteins. In turn, growth factor pathways may modulate phosphorylation and function of steroid receptors and potentiate or inhibit the mitogenic actions of steroids. Ultimately, during the progression of the malignant mammary epithelial cell to hormonal autonomy, overexpression, mutation, or disregulation of key elements of growth factor signal transduction pathways all may play critical roles.

Animals↗
PubMed1996

Induction of ductal morphogenesis and lobular hyperplasia by amphiregulin in the mouse mammary gland.

As the juvenile mouse mammary gland matures, it undergoes extensive epithelial proliferation, leading to a network of ductal branching that transverses the organ. Recent evidence suggests that the epidermal growth factor-related peptide amphiregulin (AR) may play multiple roles in the proliferation, differentiation, and neoplastic conversion of the mouse mammary gland. Using a dual approach of recombinant AR in slow-release pellets and retroviral expression of AR, we explored the roles of this growth factor in the mouse mammary gland in vivo. We first noted that recombinant AR can reestablish longitudinal ductal proliferation in growth quiescent mammary glands of ovariectomized mice. Furthermore, retrovirally transduced mammary transplants overexpressing AR developed into hyperplastic tertiary ducts and hyperplastic lobules with increased lateral branching, apparent 9 weeks after transplantation into cleared mammary fat pads. This is the first study to demonstrate that AR can reestablish the early developmental activity of ductal mammary epithelium and induce hyperplasia in vivo. These data, coupled with previous findings that demonstrated nearly universal overexpression of AR in human breast cancer and rodent mammary tumorigenesis, suggest that AR may be an important intermediary in glandular maturation and early malignant progression.

Adipose Tissue↗
PubMed1995

Detection and location of amphiregulin and Cripto-1 expression in the developing postnatal mouse mammary gland.

Amphiregulin (Ar) and Cripto-1 (Cr-1) are growth promoting peptides that share amino acid sequence homology with epidermal growth factor (EGF). The present study examined Ar and Cr-1 mRNA and protein expression during various stages of C57BL/6 mouse mammary morphogenesis. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect transcripts for Ar and Cr-1 at all stages of mammary development. Immunocytochemical (ICC) localization demonstrated that in virgin 4-week to mature 12-week-old mouse fourth inguinal mammary gland, Ar and Cr-1 are expressed in the stromal cells, luminal epithelial cells, and myoepithelial cells of the branching ducts. Ar, and to lesser extent Cr-1, were also found in the epithelial cap cells and in the luminal epithelial cells of the advancing terminal end bud (TEB) from virgin 4-week and 6-week-old mice. Western blot analysis demonstrated that both Ar (28 and 26 kDa) and Cr-1 (90, 67, 56, and 21 kDa) proteins are expressed in virgin, 13.5 day midpregnant and in the 14 day lactating mammary gland. In addition, Ar and Cr-1 are associated with developing alveolar structures as determined by ICC. These results imply that together with EGF and transforming growth factor alpha (TGF alpha), Ar and Cr-1 may play salient roles as modifiers in the morphogenesis and differentiation of the mammary gland.

Amphiregulin↗
PubMed1994

Food aversion induced by area postrema ablation.

Rats with lesions of the area postrema (APX rats) avoid foods ingested on a regular basis during the period of severe hypophagia immediately following surgery (Tomoyasu & Kenney, 1989). The present work determined whether APX rats would also avoid foods to which they are exposed only after they have recovered from the lesion-induced hypophagia. APX and SHAM-lesion rats were fed a novel food for 8 days beginning at least 1 month after surgery when food intakes (adjusted for body weight) and weight gains of the APX rats had returned to control levels. During 24 h, two-food choice tests, APX rats avoided the food ingested a month after the ablation while avidly ingesting an alternative food, but SHAM rats showed no preference between the foods. There was no indication that this aversion developed by APX rats to foods ingested after recovery from hypophagia is weaker than that developed to foods ingested immediately after the lesion. We conclude that area postrema ablation results in the development of an unconditioned stimulus capable of supporting food-aversion conditioning which remains effective more than 1 month after the ablation. Hence, the relationship between APX-induced food aversion and hypophagia must be indirect and complex. Also, conditioning of food aversions induced by area postrema ablation alone may confound studies of the role of this structure in mediating the development of food aversions after other physiological and/or pharmacological manipulations.

Animals↗
PubMed1993

Expression of transforming growth factor alpha antisense mRNA inhibits the estrogen-induced production of TGF alpha and estrogen-induced proliferation of estrogen-responsive human breast cancer cells.

To ascertain if 17 beta-estradiol (E2)-induced proliferation could be attenuated by blocking the expression of endogenous transforming growth factor alpha (TGF alpha), estrogen receptor (ER)-positive, estrogen-responsive MCF-7 or ZR-75-1 cells and ER-negative, estrogen-nonresponsive MDA-MB-468 or HS-578T cells were infected with a recombinant amphotropic, replication-defective retroviral expression vector containing a 435 base pair (bp) Apa1-Eco R1 coding fragment of the human TGF alpha cDNA oriented in the 3' to 5' direction and under the transcriptional control of an internal heavy metal-inducible mouse metallothionein (MT-1) promoter and containing the neomycin (neo) resistance gene. E2-stimulated expression of endogenous TGF alpha mRNA was inhibited by 4-5-fold, and the production of TGF alpha protein was inhibited by 50-80% when M-1 mass-infected MCF-7 or MZ-1 mass-infected ZR-75-1 cells were treated with 0.75-1 microM CdCl2, whereas in comparably treated parental MCF-7 or ZR-75-1 cells there was no significant effect upon these parameters. E2-stimulated anchorage-dependent growth (ADG) and anchorage-independent growth (AIG) of the M-1 or MZ-1 cells was inhibited by 60-90% following CdCl2 treatment. In contrast, neither the ADG nor AIG of the parental noninfected MCF-7 or ZR-75-1 cells that were maintained in the absence or presence of E2 was affected by comparable concentrations of CdCl2. The ADG and AIG of TGF alpha antisense MD-1 mass-infected MDA-MB-468 cells that express high levels of endogenous TGF alpha mRNA were also inhibited by 1 microM CdCl2, whereas the ADG and AIG of MH-1 mass-infected HS-578T cells, a TGF alpha-negative cell line, were unaffected by CdCl2 treatment. These results suggest that TGF alpha may be one important autocrine intermediary in regulating estrogen-induced cell proliferation.

Breast Neoplasms↗
PubMed1989

Response to chronic insulin administration: effect of area postrema ablation.

The effects of daily administration of protamine zinc insulin (PZI) on plasma insulin and glucose levels and on food intake and body weight of rats with lesions of the area postrema and adjacent caudal-medial portions of the nucleus of the solitary tract (APX rats) were examined. Prior to insulin treatment, APX rats weighted less and had lower plasma immunoreactive insulin (IRI) levels than nonlesioned controls but did not differ from controls in plasma glucose levels. Five daily injections of 5 U/kg PZI raised plasma IRI and lowered plasma glucose levels similarly for both lesioned and nonlesioned rats. When injected with increasing doses of PZI over a 30-day period, both lesioned and nonlesioned rats showed increases of food intake and rate of weight gain in response to 8 U/kg PZI. These data indicate that APX does not affect either physiological or behavioral responses to chronic peripheral insulin administration.

Animals↗
PubMed1989

Body weight of rats following area postrema ablation: effect of early force-feeding.

This study examined the effect of intragastric force-feeding of a milk diet on body weights of rats with lesions of the area postrema/caudal medial nucleus of the solitary tract (AP/cmNTS). Force-feeding was conducted over the first 10 days after the ablation. Body weight was monitored both during and after force-feeding. Food intake was measured during all ad libitum feeding periods. During force-feeding, rats with AP/cmNTS lesions gained weight at the same rate as force-fed sham-lesioned rats or sham-lesioned rats that voluntarily ingested an equal amount of the milk. When returned to ad libitum feeding, lesioned rats that had been force-fed were not hypophagic and did not lose weight. Body weights of such rats remained above those of lesioned rats that were not force-fed and similar to those of nonlesioned rats throughout this study. Despite their normal weights, preliminary analysis indicated that body fat of the force-fed lesioned rats may have been reduced. These findings suggest that the effects of AP/cmNTS ablation are multiple and that reduction of body weight need not be the primary effect of such lesions.

Animals↗
PubMed1989

Response to palatability after area postrema lesions: a result of learned aversions.

The role of palatability, novelty, and food aversion in determining changes of food choice after ablation of the area postrema and caudal-medial aspect of the nucleus of the solitary tract (AP/cmNTS) is examined through a series of studies utilizing 24-h, two-food choice tests. On test days, the food that the animal has ingested since the time of lesioning or sham surgery is presented along with a novel food that varies in palatability. The results indicate that postlesion diet history is the major determinant of food choice by lesioned rats. Lesioned rats consistently take less of their familiar postlesion food than diet-matched controls, suggesting that the lesioned rats have developed an aversion to that food. Over-ingestion of the novel food may occur, but this outcome is not reliable. No indication that the animals' response to food palatability is affected by AP/cmNTS ablation was found. Learned aversion to a food ingested after AP/cmNTS ablation may account not only for changes of food preference after the lesion but also may be involved in the hypophagia and weight loss resulting from the ablation.

Animals↗
PubMed1986

Ovarian steroid manipulation of the antidipsogenic and thermogenic responses of rats to central administration of prostaglandin E1.

Intracerebroventricular (icv) injection of prostaglandin E1 (PGE1) increases arterial pressure, suppresses water intake, and elevates core temperature of rats. Treatment of ovariectomized rats with estradiol or progesterone results in an attenuation of the pressor response to PGE1. This work addressed the effects of daily subcutaneous injection of estradiol (1 microgram), progesterone (5 mg), or oil vehicle on the antidipsogenic and thermogenic response to icv PGE1 of ovariectomized rats. The change of core temperature induced by the PGE treatment was significantly correlated with antidipsogenesis for ovariectomized rats receiving daily oil injections. Although neither the suppression of water intake nor the increase of core temperature in response to icv PGE1 was affected significantly by ovarian steroid treatment, the linear relation between the thermogenic and antidisogenic actions of the icv PGE1 was abolished by either estradiol or progesterone administration. Thus, although the pressor, antidipsogenic, and thermogenic effects of icv PGE1 tend to occur in concert, they may be differentially affected by ovarian steroid administration, which suggests that the mechanisms underlying these varied effects of icv PGE1 may be independent.

Alprostadil↗
PubMed1984

Diet selection following area postrema/nucleus of the solitary tract lesions.

Ten adult Long-Evans male rats were offered access to fat, protein and carbohydrate from separate sources. After adaptation to this diet, 5 animals received thermal lesions of the area postrema and adjacent caudal-medial portion of the nucleus of the solitary tract (AP/cmNTS). The remainder were sham-operated. AP/cmNTS lesioned rats ate significantly less and lost more weight than controls during the first postsurgery measurement period (Days 4-13 after lesioning). The decrease of food intake of AP/cmNTS lesioned rats was due to reduced fat consumption. Carbohydrate and protein intakes of lesioned animals did not differ from those of controls. Food intakes and weight changes of lesioned rats did not differ from those of controls during days 14-23 after lesioning. Intake of fat by lesioned animals remained low but was no longer significantly different from that of controls. Carbohydrate and protein intakes of lesioned rats increased slightly but did not differ significantly from those of nonlesioned controls.

Animals↗
PubMed1984

Area postrema/nucleus of the solitary tract ablations: analysis of the effects of hypophagia.

The effect of hypophagia following lesions of the area postrema and caudal-medial aspect of the nucleus of the solitary tract AP/cmNTS) on body-weight, water intake and preference for palatable diets was examined. Following AP/cmNTS ablation, rats reduced pelleted-food intake to a degree which was sufficient to account for the weight loss and increased water:food ratios observed. Restricting food intakes of intact rats to levels taken by lesioned animals resulted in similar weight losses and increased water:food ratios. When offered both pelleted food and milk, lesioned rats took more calories as milk than did previously food-restricted intact rats. Thus, the hypophagia of AP/cmNTS lesioned rats does not account for their increased preference for milk diets. Lesioned rats ate less high-fat diet than did intact or sham-lesioned controls and did not increase their intakes when this diet was sweetened. At autopsy, retroperitoneal and epididymal fat-pad weights accounted for less of the total body weight of lesioned animals than controls suggesting that body-fat levels are reduced following AP/cmNTS ablation.

Adipose Tissue↗
PubMed1983

Changes of mean arterial pressure of the rat resulting from intracerebroventricular injections of prostacyclin or 6-keto-prostaglandin F1 alpha.

Repeated intracerebroventricular injections of 1 microgram prostacyclin reduce mean arterial pressure of conscious normotensive rats and reverse the elevation of blood pressure of conscious rats resulting from the intraventricular injection of angiotensin II. The reduction of blood pressure of normotensive rats by prostacyclin is enhanced by pretreatment with probenecid, an inhibitor of fatty-acid transport across biological membranes. Although probenecid does not completely inhibit the transport of fatty acids from the brain to the periphery, the greater effectiveness of prostacyclin in probenecid-treated animals suggests that centrally injected prostacyclin need not leak into the periphery to reduce blood pressure. When the dose of prostacyclin is reduced to 100 ng repeated each minute for 10 min, no change of blood pressure of normotensive rats is observed. The failure of the lower dose of prostacyclin to reduce blood pressure may be due to its rapid degradation. Ventricular injections of 6-keto-prostaglandin F1a, a major product of prostacyclin metabolism, causes an increase of blood pressure which may counteract the action of prostacyclin itself.

6-Ketoprostaglandin F1 alpha↗
PubMed1983

Pressor responses to central angiotensin II, prostaglandin E1 and prostaglandin E2. Effects of ovarian steroids.

The effects of ovarian steroids on baseline blood pressure and on changes of mean arterial pressure in response to centrally administered angiotensin II, prostaglandin E1, and prostaglandin E2 were examined. Ovariectomized rats treated with estradiol or progesterone showed no change of resting blood pressures relative to oil-treated, ovariectomized controls. Intracerebroventricular injections of prostaglandin E1, prostaglandin E2 or angiotensin II produced significant elevations of arterial pressure of oil-treated rats. Either estradiol or progesterone treatment significantly attenuated pressor responses to prostaglandin E1 but not to prostaglandin E2 or angiotensin II injections. The duration of the blood pressure increase of estradiol-treated rats in response to angiotensin II was reduced when the animals did not have access to drinking water during the pressure monitoring session but not when water was available. These results suggest that the effects of ovarian steroids in modulating pressor responses are dependent on the particular factors which initiate the pressure increases. Possible mechanisms underlying this ovarian-steroid action are discussed.

Alprostadil↗
PubMed1982

Cellular dehydration and hypovolemia: effect of acetylsalicylic acid on drinking.

Chronic oral administration of acetylsalicylic acid (ASA), an inhibitor of prostaglandin synthesis, reduces the latency with which rats begin drinking in response to hypovolemia but has no effect on the total amount of water consumed to this stimulus. When drinking is due to cellular dehydration, latency to drink is unaffected while total water intake is markedly augmented by ASA-pretreatment. Chronic, low-dose exposure to ASA or indomethacin has no effect on plasma levels of the dipsogen, angiotensin II. These data, taken in conjunction with previous work demonstrating a suppression of drinking following administration of exogenous prostaglandin E, support the contention that the E prostaglandins are involved in the physiological control of water intake, but suggest that the precise role of the prostaglandin in controlling consumption is dependent upon the stimulus eliciting the behavior.

Angiotensin II↗
PubMed1981

The antidipsogenic action of peripheral prostaglandin E2.

Intraperitoneal (IP) injection of 50 micrograms/kg prostaglandin E2 (PGE2) suppresses water intake elicited by cellular dehydration, intracerebroventricular injection of angiotensin II (A II) and, for a shorter duration, water deprivation. At a dose of 100 micrograms/kg, IP PGE2 reduces drinking to all of these stimuli as well as to hypovolemia. A 10 microgram/kg dose of PGE2 has no effect on drinking under any of the conditions tested. Intraperitoneal PGE2, at either 50 or 100 micrograms/kg, does not support the formation of a conditioned taste aversion suggesting that PGE may act via specific inhibition of drinking rather than by producing a generalized malaise. Although both central and peripheral administration of PGE suppresses water intake, the findings that peripheral PGE2 reduces drinking to cellular dehydration but has minimal effects on drinking due to hypovolemia are in marked contrast to the actions reported for intracranial PGE. In addition, peripheral PGE2 reduces body temperature whereas centrally applied PGE induces thermogenesis. These data may indicate differential roles and/or mechanisms by which central and peripheral PGE may control water intake.

Angiotensin II↗
PubMed1981

The role of endogenous prostaglandin E in angiotensin-II-induced drinking in rats.

Oral administration of indomethacin, a nonsteroidal anti-inflammatory agent which suppresses endogenous prostaglandin E2 (PGE2) levels in plasma, results in an augmentation of total water intake and a shortening of the latency to drink in response to an intravenous infusion of angiotensin II. This same treatment has no effect on water intake stimulated by the intracranial injection of the dipsogen. Plasma PGE2 may act as both a tonic inhibitor of drinking and a satiety indicator in situations in which water intake is stimulated by increases in blood levels of angiotensin II. While peripheral PGE2 levels do not appear to be involved in the control of drinking to increased brain levels of angiotensin II, the role of endogenous central PGE in this phenomenon remains unknown.

Angiotensin II↗