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Biomedical subjects

P A Furth

Publications and source records attributed to P A Furth.

At least 19 recordsLinked to original sources
PubMed2004

Bax regulates c-Myc-induced mammary tumour apoptosis but not proliferation in MMTV-c-myc transgenic mice.

The expression of the proto-oncogene c-myc is frequently deregulated, via multiple mechanisms, in human breast cancers. Deregulated expression of c-myc contributes to mammary epithelial cell transformation and is causally involved in mammary tumorigenesis in MMTV-c-myc transgenic mice. c-Myc is known to promote cellular proliferation, apoptosis, genomic instability and tumorigenesis in several distinct tissues, both in vivo and in vitro. Expression of the proapoptotic regulatory gene bax is reduced or absent in human breast cancers, and c-Myc has been shown to regulate the expression of Bax, as well as cooperate with Bax in controlling apoptosis in a fibroblast model. Additionally, loss of bax reduces c-Myc-induced apoptosis in lymphoid cells and increases c-Myc-mediated lymphomagenesis in vivo. In order to assess whether loss of bax could influence c-Myc-induced apoptosis and tumorigenesis in the mammary gland in vivo, we generated MMTV-c-myc transgenic mice in which neither, one, or both wild-type alleles of bax were eliminated. Haploid loss of bax in MMTV-c-myc transgenic mice resulted in significantly reduced mammary tumour apoptosis. As anticipated for an apoptosis-regulatory gene, loss of the wild-type bax alleles did not significantly alter cellular proliferation in either mammary adenocarcinomas or dysplastic mammary tissues. However, in contrast to c-Myc-mediated lymphomagenesis, loss of one or both alleles of bax in MMTV-c-myc transgenic mice did not significantly enhance mammary tumorigenesis, despite evidence that haploid loss of bax might modestly increase mammary tumour multiplicity. Our results demonstrate that Bax contributes significantly to c-Myc-induced apoptosis in mammary tumours. In addition, they suggest that in contrast to c-Myc-induced lymphomagenesis, mammary tumorigenesis induced by deregulated c-myc expression requires some amount of Bax expression.

Animals↗
PubMed2001

The Stat3/5 locus encodes novel endoplasmic reticulum and helicase-like proteins that are preferentially expressed in normal and neoplastic mammary tissue.

The signal transducers and activators of transcription (STAT) 5 and 3 are critical for mammary alveolar development during pregnancy and remodeling during involution. In the mouse, STAT3, STAT5a, and STAT5b are encoded by adjacent genes on chromosome 11 (60.5 cM). To identify additional genes in the Stat3/5 locus that may participate in normal and neoplastic development of the mammary gland, we have cloned and sequenced 500 kb and searched for genes preferentially expressed in mammary tissue. We identified six known genes and cloned two new genes, termed D11Lgp1 and D11Lgp2. Both genes are most highly expressed in normal mammary tissue and mammary tumors from several transgenic mouse models. LGP1 consists of 532 and 530 amino acids in mouse and human, respectively (88% similarity). A region in the carboxy-terminal half of LGP1 has limited homology with Arabidopsis thaliana GH3-like proteins. Immunofluorescence studies demonstrated that LGP1 is located in the nuclear envelope and the endoplasmic reticulum. LGP2 is a cytoplasmic protein of 678 amino acids.

Amino Acid Sequence↗
PubMed2001

Genetic interactions between tumor suppressors Brca1 and p53 in apoptosis, cell cycle and tumorigenesis.

Breast cancer is a chief cause of cancer-related mortality that affects women worldwide. About 8% of cases are hereditary, and approximately half of these are associated with germline mutations of the breast tumor suppressor gene BRCA1 (refs. 1,2). We have previously reported a mouse model in which Brca1 exon 11 is eliminated in mammary epithelial cells through Cre-mediated excision. This mutation is often accompanied by alterations in transformation-related protein 53 (Trp53, encoding p53), which substantially accelerates mammary tumor formation. Here, we sought to elucidate the underlying mechanism(s) using mice deficient in the Brca1 exon 11 isoform (Brca1Delta11/Delta11). Brca1Delta11/Delta11 embryos died late in gestation because of widespread apoptosis. Unexpectedly, elimination of one Trp53 allele completely rescues this embryonic lethality and restores normal mammary gland development. However, most female Brca1Delta11/Delta11 Trp53+/- mice develop mammary tumors with loss of the remaining Trp53 allele within 6-12 months. Lymphoma and ovarian tumors also occur at lower frequencies. Heterozygous mutation of Trp53 decreases p53 and results in attenuated apoptosis and G1-S checkpoint control, allowing Brca1Delta11/Delta11 cells to proliferate. The p53 protein regulates Brca1 transcription both in vitro and in vivo, and Brca1 participates in p53 accumulation after gamma-irradiation through regulation of its phosphorylation and Mdm2 expression. These findings provide a mechanism for BRCA1-associated breast carcinogenesis.

Animals↗
PubMed2001

In utero and lactational treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin impairs mammary gland differentiation but does not block the response to exogenous estrogen in the postpubertal female rat.

These experiments tested whether in utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters mammary gland differentiation, estrogen receptor alpha (ERalpha) expression levels, or the response to estrogen in the female postpubertal rat mammary gland. Pregnant Holtzman rats were administered a single oral dose of 1 microg/kg TCDD or vehicle on gestation-day 15. Exposed and non-exposed female offspring were weaned on postnatal day 21 and ovariectomized at 9 weeks of age. Two weeks later, both TCDD and control animals were divided into 3 groups, receiving treatment with placebo, 0.025, or 0.1 mg 17beta-estradiol pellet implants. After 48 h, mammary tissue was removed for analysis following euthanasia. TCDD-exposed mammary glands demonstrated impaired differentiation as measured by the distribution of terminal ductal structures and increased expression levels of ERalpha. The response to exogenous estrogen was tested in TCDD-exposed animals and compared to control non-exposed animals. Estrogen stimulation of the TCDD-exposed glands induced progesterone receptor expression and mammary gland differentiation as measured by a shift in distribution from terminal end buds and terminal ducts to Types I and II lobules. Control glands were better differentiated at baseline and did not exhibit any significant changes in the distribution of terminal ductal structures following estrogen stimulation. The increase in progesterone receptor-expression levels by exogenous estrogen in control glands was similar to the TCDD-exposed glands. These experiments demonstrate that in utero and lactational exposures to TCDD impair mammary gland differentiation but that TCDD-exposed mammary glands retain the ability to differentiate in response to estrogen.

Actins↗
PubMed2001

Effect of bcl-2 on the primordial follicle endowment in the mouse ovary.

Little is known about the embryonic factors that regulate the size of the primordial follicle endowment at birth. A few studies suggest that members of the B-cell lymphoma/leukemia-2 (bcl-2) family of protooncogenes may be important determinants. Thus, the purpose of this study was to test whether bcl-2 regulates the size of the primordial follicle pool at birth. To test this hypothesis, three lines of transgenic mice (c-kit/bcl-2 mice) were generated that overexpress human bcl-2 in an effort to reduce prenatal oocyte loss. The overexpression was targeted to the ovary and appropriate embryonic time period with the use of a 4.8-kilobase c-kit promoter. This promoter provided two to three times more expression of bcl-2 in the ovaries with minimal or no overexpression in most nongonadal tissues. On Postnatal Days 8-60, ovaries were collected from homozygous c-kit/bcl-2 and nontransgenic littermates (controls) and processed for histological evaluation of follicle numbers. All lines of c-kit/bcl-2 mice were born with significantly more primordial follicles than control mice (P < or = 0.05). By Postnatal Days 30-60, however, there were no significant differences in follicle numbers between c-kit/bcl-2 and control mice. These results indicate that bcl-2 overexpression increases the number of primordial follicles at birth, but that the surfeit of primordial follicles is not maintained in postnatal life. These data suggest that it is possible that the ovary may contain a census mechanism by which excess numbers of primordial follicles at birth are detected and removed from the ovary by adulthood.

Animals↗
PubMed2001

A simplified method to prepare PCR template DNA for screening of transgenic and knockout mice.

Polymerase chain reaction (PCR) amplification of DNA is the most widely used technique for screening of large numbers of genetically engineered transgenic or knockout mice (Mus musculus). In this report, we present a new DNA preparation procedure for running diagnostic PCR. In this procedure, mouse ear tissue was used directly for PCR after the tissue underwent brief digestion in a solution containing only proteinase K. Using this method, we have successfully screened several lines of single, double, and triple transgenic and knockout mice. The results are reliable and reproducible. The advantage of this new method is that DNA purification by organic extraction or isolation kit was omitted. DNA purification is the limiting factor in terms of time and money when screening transgenic and knockout mice by PCR. In addition, using ear instead of tail tissue can reduce distress of animals because the samples can be obtained when the mice are labeled by ear punch.

Animal Identification Systems↗
PubMed2000

Reduced mammary tumor progression in WAP-TAg/WAP-maspin bitransgenic mice.

Maspin is a unique serpin involved in the suppression of tumor growth and metastasis. To investigate whether increased levels of maspin protect against tumor progression in vivo, we established a transgenic model in which maspin is targeted to mammary epithelial cells by the Whey Acidic Protein (WAP) promoter for overexpression. We crossed these WAP-maspin transgenic mice with the WAP-TAg mouse model of tumor progression. Maspin overexpression increased the rate of apoptosis of both preneoplastic and carcinomatous mammary epithelial cells. Maspin reduced tumor growth through a combination of reduced angiogenesis and increased apoptosis. The number of pulmonary metastases was reduced in the presence of maspin overexpression. These data demonstrate that targeted overexpression of maspin can inhibit tumor progression in vivo, likely through a combination of increased apoptosis, decreased angiogenesis, and inhibition of tumor cell migration.

Adenocarcinoma↗
PubMed2000

Induction of bcl-xL expression in mammary epithelial cells is glucocorticoid-dependent but not signal transducer and activator of transcription 5-dependent.

In the present study, we examined the role of prolactin and glucocorticoids in regulating bcl-x transcription in mammary epithelial cells. We report that dexamethasone, but not prolactin, induced native bcl-x gene expression in a dose-dependent manner in HC11 cells and enhanced serum-starved HC11 cell survival. This effect was mediated through the glucocorticoid receptor and independent of STAT-5 activity. We propose that the mechanism through which glucocorticoids enhance mammary epithelial cell survival is by increasing steady-state levels of bcl-xL, RNA.

Animals↗
PubMed2000

WAP-TAg transgenic mice and the study of dysregulated cell survival, proliferation, and mutation during breast carcinogenesis.

Understanding the process of carcinogenesis is key to developing therapies which might interrupt or reverse tumor onset and progression. Cell growth and death signals are dependent not only upon molecular mechanisms within a cell but also upon external stimuli such as hormones, cell - cell signaling, and extracellular matrix. Mouse models can be used to dissect these complex processes, to identify key signaling pathways operating at different stages of tumorigenesis, and to test the strength of specific interventions. In the WAP-TAg mouse model, carcinogenesis is initiated by expression of the Simian Virus 40 T antigen (TAg). TAg expression is triggered by hormonal stimulation, either during estrus or pregnancy. Breast adenocarcinomas (ranging from well to poorly differentiated) develop in 100% of the female mice by approximately 8 - 9 months of age. Three distinct stages of tumorigenesis are easily identified: an initial proliferation, hyperplasia, and adenocarcinoma. The mean time to first palpable tumor in mice which undergo at least one pregnancy is 6 months. The tumorigenic process is marked by a competition between proliferation and apoptosis and is characterized by cellular acquisition of genetic mutations and increased stromal fibrosis. Protein levels of cell cycle control genes cyclin D1, cdk2, and E2F-1 are increased in these adenocarcinomas. c-Fos protein levels are slightly increased in these cancers, while c-Jun levels do not change. Hormonal exposure alters progression. Estrogen plays a role during the early stages of oncogenesis although the growth of the resulting adenocarcinomas is estrogen-independent. Transient hormonal stimulation by glucocorticoids that temporarily increases the rate of cell proliferation results in tetraploidy, premature appearance of irreversible hyperplasia, and early tumor development. Tumor appearance also can be accelerated through over expression of the cell survival protein, Bcl-2. Bcl-2 over expression not only reduces apoptosis during the initial proliferative process but also decreases the total rate of cell proliferation. This block in cell proliferation is lost selectively as the cells transition to adenocarcinoma. The WAP-TAg model can be utilized to investigate how the basic processes of cell proliferation, apoptosis, DNA mutation, and DNA repair are modified by external and internal signals during mammary oncogenesis.

Animals↗
PubMed2000

Environmental factors in infertility.

In conclusion, several studies indicate that there is an association between cigarette smoking and adverse reproductive outcomes in women as well as men. Some studies indicate that alcohol consumption impairs the reproductive capacity of women. Exposures to PCE in the dry cleaning industry, toluene in the printing business, ethylene oxide and mixed solvents have been associated with decreased fecundity. Abnormalities in sperm production have been found in men exposed to radiant heat or heavy metals. Environmental exposure to chlorinated hydrocarbons (e.g., DDT, PCB, pentachlorophenol, hexachlorocyclohexane) has been associated with an increase in rates of miscarriage and endometriosis. Clinicians should counsel patients who are trying to achieve a successful pregnancy to stop smoking and limit alcohol intake. Clinicians can additionally counsel patients who are in contact with potentially harmful occupational and environmental toxicants to limit their exposure. It is important to recognize, however, that many of the studies to date are limited by small sample size, poor exposure assessment, poor outcome measurements, recruitment bias, or recall bias. Additional studies will be necessary to clarify the magnitude of risk associated with these factors.

Alcohol Drinking↗
PubMed1999

Loss of anti-mitotic effects of Bcl-2 with retention of anti-apoptotic activity during tumor progression in a mouse model.

Bcl-2 is an anti-apoptotic and anti-proliferative protein over-expressed in several different human cancers including breast. Gain of Bcl-2 function in mammary epithelial cells was superimposed on the WAP-TAg transgenic mouse model of breast cancer progression to determine its effect on epithelial cell survival and proliferation at three key stages in oncogenesis: the initial proliferative process, hyperplasia, and cancer. During the initial proliferative process, Bcl-2 strongly inhibited both apoptosis and mitotic activity. However as tumorigenesis progressed to hyperplasia and adenocarcinoma, the inhibitory effects on mitotic activity were lost. In contrast, anti-apoptotic activity persisted in both hyperplasias and adenocarcinomas. These results demonstrate that the inhibitory effect of Bcl-2 on epithelial cell proliferation and apoptosis can separate during cancer progression. In this model, retention of anti-apoptotic activity with loss of anti-proliferative action resulted in earlier tumor presentation.

Adenocarcinoma↗
PubMed1999

Gain of Bcl-2 is more potent than bax loss in regulating mammary epithelial cell survival in vivo.

The impact of gain of Bcl-2 function on mammary epithelial cell survival was compared with loss of Bax function during the two stages of mammary gland involution. Bcl-2 gain of function reduced apoptosis 50% during the first stage and increased cell survival 70% during the second stage. Complete loss of Bax reduced apoptosis by 20% during the first stage without second stage effect. Partial loss of Bax was ineffective but increased cell survival 2.4-fold when combined with Bcl-2 gain. Gain of Bcl-2 function is more potent than loss of Bax function in regulating mammary epithelial cell survival in vivo.

Animals↗
PubMed1999

Bcl-2 gene family and related proteins in mammary gland involution and breast cancer.

The Bcl-2 gene family regulates tissue development and tissue homeostasis through the interplay of survival and death factors. Family members are characterized as either pro-apoptotic or anti-apoptotic, depending on cellular context. In addition to its anti-apoptotic effect, Bcl-2 also inhibits progression through the cell cycle. Functional interactions between family members as well as binding to other cellular proteins modulate their activities. Mammary gland tissue, similar to many other tissues, expresses a number of different Bcl-2 relatives including bcl-x, bax, bak, bad, bcl-w, bfl-1, bcl-2 as well as the bcl-2 binding protein Bag-1. Bcl-2 is expressed in the nonpregnant mammary gland and early pregnancy. In contrast, expression of bcl-x and bax continues through late pregnancy, is down-regulated during lactation, and upregulated with the start of involution. Bak, bad, bcl-w, and bfl-1 are also up-regulated during involution. The specific roles of individual gene products are investigated using dominant gain of function and loss of function mice. Finally, different Bcl-2 family members are commonly over- or under-expressed in human breast cancers. Bcl-2 expression in human breast cancers has been associated with a good prognosis, while decreased Bax expression has been linked to poor clinical outcome. Understanding the role Bcl-2 family members play in regulating mammary epithelial cell survival is salient to both normal mammary gland physiology and the development of new therapeutic approaches to breast cancer.

Animals↗
PubMed1999

A pilot study of a headache program in the workplace. The effect of education.

Headache is a frequent problem in the workplace and contributes to absenteeism and productivity loss. Disease-management programs targeting headache may reduce its impact on employees, employers, and society. A pilot study was conducted in an employer setting (J.P. Morgan & Co., Incorporated; four locations in New York City and two in Delaware) to evaluate a multimedia computer-based (kiosk) headache program. Study objectives included assessing the effect of the program on participant outcomes and evaluating the educational component of the program. Through the kiosk, participants were questioned about the types, severity, and frequency of their headaches; the impact of headaches on their daily activities; and lost workdays as a result of headache. All participants received personalized reports about their headaches, and the participants in New York were given access to an on-site neurologist and additional educational information. A follow-up assessment was requested 3 months after the baseline screening to evaluate the effect of the program. A total of 185 participants completed both a baseline and follow-up session. Of 177 evaluable participants, 19% saw a physician for headache after their initial kiosk session. Fifty-six percent of evaluable participants reported overall improvement in headache symptoms at follow-up (P < 0.01), with decreased headache frequency and better understanding of headache most often selected as reasons for improvement. Participants also reported higher satisfaction with headache management after using the program and fewer urgent care/emergency room visits for headache (P < 0.01). For participants who reported lost workdays because of headache, the number of days missed had decreased by the follow-up. The results of this study indicate that the headache program improved outcomes. Because all participants received educational materials, it is likely that education played a role in the improvements observed. These results are encouraging and warrant further study in larger, controlled trials.

Adult↗
PubMed1998

Studying development of disease through temporally controlled gene expression in the salivary gland.

Multistep tumorigenesis proceeds through activation of oncogenes and inactivation of tumor suppressor genes. Initiating oncoproteins induce secondary changes that maintain transformation in the absence of original stimuli. Time-dependent reversal of SV40 T antigen (TAg)-induced hyperplasia was studied using temporally controlled gene expression. Targeting TAg expression to the submandibular salivary gland of transgenic mice produces focal hyperplasias at age two weeks, which extend through large areas of the gland by four months. At twelve months, fibrosis and tumor foci accompany hyperplasia. Hyperplasia reverses when TAg expression in discontinued at four months but not at seven months. Secondary changes that maintain transformation appear to be time dependent. The system can be used to identify genetic events resulting in phenotypic reversal at four months and to expose factors preventing its occurrence at seven months. Expression of other proteins can be targeted to the salivary gland, and temporally controlled gene deletions can also be made using this system.

Animals↗