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Biomedical subjects

P Pujol

Publications and source records attributed to P Pujol.

At least 19 recordsLinked to original sources
PubMed2006

From adjuvant to preventive breast cancer treatment: bridging the gap over troubled waters.

Recently, chemoprevention trials have demonstrated the efficacy of preventive medical treatment (PMT) in reducing breast cancer (BC) detection rates in at-risk affected and unaffected women selected according to clinical and/or familial risk criteria, particularly with the use of tamoxifen (TAM). Major concerns limiting the routine use of TAM are the questionable benefit/risk ratio and poor patient compliance, which justify the studies undertaken to determine the efficacy of aromatase inhibitors (AIs) with respect to TAM. Issues such as therapy duration, impact on survival, incidence of side-effects and which subsets benefit most from treatment, still remain unsolved. Therefore, only ER+ BC patients are routinely subjected to PMT, independently of their BRCA1/2 status, using adjuvant hormonal therapy. More attention must be focused towards BRCA1/2 carriers as they are probably the women at highest risk of developing BC, in which available data remain controversial and in which hormone-therapy might be important. Hence, at-risk women (affected patients or unaffected women) should be carefully evaluated for inclusion into highly selected preventive clinical trials aimed at evaluating PMT independently of, or according to, BC predisposition status (unknown, positive or negative BRCA1/BRCA2 status) and with respect to menopausal status. BC patients, harboring a BRCA1/2 predisposition, may represent the best subset for extended adjuvant treatment, useful as PMT, simultaneously. Only the evolving differentiation of categories of at-risk women will allow physicians to discriminate PMT in a highly selective manner.

Breast Neoplasms↗
PubMed2006

Chordin is underexpressed in ovarian tumors and reduces tumor cell motility.

Ovarian cancers mostly derive from the monolayer epithelium that covers the ovary. There are currently very few molecular clues to the etiology of this cancer. Bone morphogenetic proteins (BMPs) are required for follicular development and female fertility and are expressed in the ovarian surface epithelium (OSE). We previously reported the expression of human chordin (CHRD), a BMP extracellular regulator, in the ovary. Here we show that CHRD is underexpressed in epithelium ovary cancer and epithelial cancer cell lines as compared with normal tissues and OSE, respectively. Besides, we detected BMP expression in all ovarian cell lines analyzed. To determine the functional relevance of the absence of CHRD mRNA in tumors and cancer cell lines, we studied the effects of CHRD on two cancer cell lines, BG1 and PEO14. Migratory and invasive properties were greatly reduced, whereas cell adhesion to the support was enhanced. In addition, we detected chordin (Chrd) expression in OSE of rat ovaries in a pattern similar to that of BMP4. Altogether, these results suggest that CHRD could participate in regulating BMP activity in normal OSE physiology, and that its mis-expression in OSE may facilitate cancer incidence and/or progression.

Animals↗
PubMed2005

[Hereditary predispositions to gynaecological cancers].

The breast, ovary and endometrial cancers are hereditary in 5 to 10% of the cases. These genetic predisposition syndromes can be classified into two major classes: ovarian cancer and breast cancer predisposition family cases (genes BRCA1 and BRCA2) and family cases of colon cancer, endometrial cancer and ovarian cancer (Lynch syndrome or HNPCC) (genes hMLH1, hMSH2, hMLH6). The estimate of the family and individual risk can contribute in a determining manner to the management of these patients, by the practice of screening or an adapted prevention. Indeed, the risk of cancer of an individual having a positive test for a gene of predisposition to breast cancer (BRCA1, BRCA2) or to the colon cancer (hMLH1, hMSH2, hMLH6) lies between 50 and 70% at the age of 70 years. The indication of a genetic test must be discussed within the framework of an oncogenetic consultation. An individual and family medical management ranging from simple monitoring to prophylactic surgery is proposed to these predisposed people.

Adaptor Proteins, Signal Transducing↗
PubMed2005

[Multivisceral resections of extracolorectal lesions in familial adenomatous polyposis].

AIMS: 1/ To report our experience with multivisceral resections in familial adenomatous polyposis (FAP) for extracolorectal lesions in a cohort of nine patients. 2/ Discuss the long term results of an agressive surgery. PATIENTS AND METHODS: Nine patients (7 males and 2 females) were operated at the University Hospital of Nimes (N=4) and Nantes (N=5). The median age at the first operation was 29 years (range 18-43). A genetic study was performed in six patients and confirmed the mutation on APC gene (exon 11, 13 and 15). All the patients were operated through a classic laparotomy. RESULTS: All patients have underwent a mean of three operations (range 2-5). Eight patients have had initially a total colectomy and 4 underwent subsequent proctectomy. Seven patients had pancreaticoduodenectomy for extensive duodenal adenomas and/or carcinoma. Three had one or multiple small bowel resections for development of carcinoma and one had partial gastric resection for large adenovillous tumor. The median follow up was 25 years (range 15-37) since the first operation. Three patients were died: one of gastric cancer with hepatic metastases, one of peritoneal carcinosis after ileal resection and one of astrocytoma. CONCLUSION: With regard to these nine observations, the authors underline the possibility of multivisceral resection in FAP. Despite a major digestive mutilation, it permits a long survival with acceptable quality of life. The prognosis depends on the aggressiveness of the duodenal or jejunoileal lesions more than of the colorectal tumors if found at the first resection.

Adenoma↗
PubMed2005

Aromatase expression in ovarian epithelial cancers.

Our study focused on aromatase cytochrome P450 (CYP19) expression in ovarian epithelial normal and cancer cells and tissues. Aromatase mRNA expression was analyzed by real-time PCR in ovarian epithelial cancer cell lines, in human ovarian surface epithelial (HOSE) cell primary cultures, and in ovarian tissue specimens (n=94), including normal ovaries, ovarian cysts and cancers. Aromatase mRNA was found to be expressed in HOSE cells, in BG1, PEO4 and PEO14, but not in SKOV3 and NIH:OVCAR-3 ovarian cancer cell lines. Correlation analysis of aromatase expression was performed according to clinical, histological and biological parameters. Aromatase expression in ovarian tissue specimens was higher in normal ovaries and cysts than in cancers (P<0.0001). Using laser capture microdissection in normal postmenopausal ovaries, aromatase was found to be predominantly expressed in epithelial cells as compared to stromal component. Using immunohistochemistry (IHC), aromatase was also detected in the epithelium component. There was an inverse correlation between aromatase and ERalpha expression in ovarian tissues (P<0.001, r=-0.34). In the cancer group, no significant differences in aromatase expression were observed according to tumor histotype, grade, stage and survival. Aromatase activity was evaluated in ovarian epithelial cancer (OEC) cell lines by the tritiated water assay and the effects of third-generation aromatase inhibitors (AIs) on aromatase activity and growth were studied. Letrozole and exemestane were able to completely inhibit aromatase activity in BG1 and PEO14 cell lines. Interestingly, both AI showed an antiproliferative effect on the estrogen responsive BG1 cell line co-expressing aromatase and ERalpha. Aromatase expression was found in ovarian epithelial normal tissues and in some ovarian epithelial cancer cells and tissues. This finding raises the possibility that some tumors may respond to estrogen and provides a basis for ascertaining an antimitogenic effect of AI in a subgroup of ovarian epithelial cancers.

Androstadienes↗
PubMed2004

Transcriptional and posttranscriptional regulation of fibulin-1 by estrogens leads to differential induction of messenger ribonucleic acid variants in ovarian and breast cancer cells.

Fibulin-1 is an extracellular matrix protein overexpressed in epithelial ovarian and breast cancers. In estrogen receptor (ER)-positive ovarian and breast cancer cell lines, fibulin-1 mRNA levels are markedly increased by estrogens. Transfection experiments using fibulin-1 promoter constructs indicate that 17beta-estradiol (E2) increases fibulin-1 gene transcription and that ERalpha is more potent than ERbeta to mediate E2 regulation of the transfected fibulin-1 promoter. Using SL2 cells devoid of specificity protein 1 (Sp1) and site-directed mutagenesis of GC boxes, we evidenced that the E2 regulation occurs through a proximal specificity protein 1 binding site. In addition, we show that fibulin-1C and -1D mRNAs, the two major fibulin-1 splicing variants, are differentially induced by E2. The induction of both mRNAs variants is direct and independent of a newly synthesized protein intermediate. Interestingly, actinomycin D chase experiments demonstrate that E2 treatment selectively shortens the fibulin-1D mRNA half-life. This indicates that estrogens affect differentially the stability of fibulin-1 variants and may explain the lower accumulation of fibulin-1D mRNA on E2 treatment. In conclusion, our data show that estrogens, via ERalpha, are key regulators of fibulin-1 expression at both the transcriptional and posttranscriptional levels. The preferential induction of the fibulin-1C variant, which is overexpressed in ovarian and breast cancer, might play an important role in estrogen-promoted carcinogenesis.

Base Sequence↗
PubMed2004

Loss of ERbeta expression as a common step in estrogen-dependent tumor progression.

The characterization of estrogen receptor beta (ERbeta) brought new insight into the mechanisms underlying estrogen signaling. Estrogen induction of cell proliferation is a crucial step in carcinogenesis of gynecologic target tissues, and the mitogenic effects of estrogen in these tissues (such as breast, endometrium and ovary) are well documented both in vitro and in vivo. There is also an emerging body of evidence that colon and prostate cancer growth is influenced by estrogens. In all of these tissues, most studies have shown decreased ERbeta expression in cancer as compared with benign tumors or normal tissues, whereas ERalpha expression persists. The loss of ERbeta expression in cancer cells could reflect tumor cell dedifferentiation but may also represent a critical stage in estrogen-dependent tumor progression. Modulation of the expression of ERalpha target genes by ERbeta or ERbeta-specific gene induction could explain that ERbeta has a differential effect on proliferation as compared with ERalpha. ERbeta may exert a protective effect and thus constitute a new target for hormone therapy, such as ligand specific activation. The potential distinct roles of ERalpha and ERbeta expression in carcinogenesis, as suggested by experimental and clinical data, are discussed in this review.

Breast Neoplasms↗
PubMed2001

Analysis of the potential contribution of estrogen receptor (ER) beta in ER cytosolic assay of breast cancer.

Estrogen receptor (ER) content is the most useful parameter for predicting hormone response therapy in breast cancer. Assays available for detecting ER in breast tumor cytosol are ligand-binding assay (LBA), which detects both ERalpha and ERbeta, and the enzymatic immunoassay (EIA), in which monoclonal antibodies are directed against ERalpha. As shown in several studies, the 2 assays correlate and both are used routinely. However, some discrepancies between the 2 assays were found and explanations remain controversial. We evaluated ERalpha and ERbeta mRNA coexpression in breast tumors in order to study whether the presence of ERbeta could account for differences between LBA and EIA in the determination of ER protein level. Using HeLa cell lines transfected with either ERalpha or ERbeta, we confirmed that EIA, using H222 and D547 monoclonal antibodies, recognizes only ERalpha expression, whereas LBA detects both isoforms. In 119 breast tumor cytosols, the correlation between ER-EIA and ER-LBA was high (r = 0.72), although some discrepancies were found. When analyzing ER mRNA expression of samples with higher LBA values, no overexpression of ERbeta mRNA relatively to ERalpha mRNA were observed. There was a difference in ERbeta/ERalpha ratio between ER-negative and ER-positive samples, with a 10-fold increased median ratio in ER-negative samples (p = 0.01). We thus confirmed that the major form of ER in breast cancer is the ERalpha at both the protein and mRNA levels. Moreover, our data do not support the hypothesis that ERbeta expression could explain differences between LBA and EIA in the determination of ER protein level.

Antineoplastic Agents, Hormonal↗
PubMed2001

Universality class of the Nishimori point in the 2D +/- J random-bond Ising model.

We study the universality class of the Nishimori point in the 2D +/- J random-bond Ising model by means of the numerical transfer-matrix method. Using the domain-wall free energy, we locate the position of the fixed point along the Nishimori line at the critical concentration value p(c) = 0.1094 +/- 0.0002 and estimate nu = 1.33 +/- 0.03. Then, we obtain the exponents for the moments of the spin-spin correlation functions as well as the value for the central charge c = 0.464 +/- 0.004. The main qualitative result is the fact that percolation is now excluded as a candidate for describing the universality class of this fixed point.

Journal Article↗
PubMed2001

A prospective prognostic study of the hormonal milieu at the time of surgery in premenopausal breast carcinoma.

BACKGROUND: Despite numerous studies, the influence of timing at surgery in relation to the menstrual cycle on the prognosis of breast carcinoma is still controversial. Most studies are retrospective, and the reliability of the menstrual history data is limited by the lack of hormonal assessment at the time of surgery. The authors prospectively studied the influence of the menstrual cycle phase as determined by circulating hormones at the time of surgery on the outcome of breast carcinoma. METHODS: A population of 360 premenopausal women with nonmetastatic breast carcinoma operated on from 1992 to 1995 was analyzed. Serum estradiol, progesterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels were assayed the day of surgery to define the menstrual cycle phase (follicular, n = 186; ovulatory, n = 24; luteal, n = 150). The mean follow-up was 48 months. RESULTS: There were no relations between the menstrual phase at surgery and tumor size, cathepsin D level, Scarff-Bloom-Richardson grade, Pg receptor (PgR), and the number of positive lymph nodes. The mean estrogen receptor level was higher during the follicular phase than in the ovulatory and luteal phases (P < 0.02). Univariate analysis of recurrence free survival (RFS) and overall survival (OS) showed no relations with the menstrual phase or the level of estradiol and progesterone at the time of surgery. High LH or FSH levels (above the medians) were associated with shorter RFS (P = 0.02 and P = 0.04, respectively) or OS (P < or = 0.01 and P = 0.01, respectively). In multivariate analysis, lymph node status, PgR status and LH level were the most significant parameters for predicting OS. There appeared to be no survival differences between menstrual cycle groups after stratification by lymph node status. CONCLUSIONS: This prospective study showed a lack of prognostic value of timing at surgery in relation to the menstrual period or to estrogen and progesterone levels in premenopausal breast carcinoma. Conversely, high gonadotropin levels could predict OS independently of other prognostic factors.

Breast Neoplasms↗
PubMed2001

Novel germline RET mutation segregating with papillary thyroid carcinomas.

The RET proto-oncogene is responsible for inherited medullary thyroid cancer syndromes. RET is also found mutated in sporadic medullary thyroid cancer (MTC) and rearranged in sporadic papillary thyroid carcinomas. Here, we describe a previously unreported germline RET mutation at codon 603 in exon 10 associated with both MTC and nonmedullary thyroid cancer (NMTC) in a kindred. RET may thus not be excluded as a potential candidate for predisposition to some forms of NMTC.

Adult↗
PubMed2001

An improved method for the determination of betaine in Echinacea products.

A rapid and sensitive HPLC method for the separation and quantification of betaine in Echinacea products has been developed. Strong cation-exchange (SCX) material was used as stationary phase, and a mixture of methanol and 50 mM choline buffer (pH 3.5) as mobile phase. After formation of the bromophenacyl derivative, betaine was detected at 254 nm with a detection limit of 0.2 microgram/ml. The method was successfully used to analyze several Echinacea market products, and significant variations in their betaine content from 0.04 to 0.64% were observed.

Betaine↗
PubMed2000

Random bond XXZ chains with modulated couplings

The magnetization behavior of q-periodic antiferromagnetic spin- 1/2 Heisenberg chains under uniform magnetic fields is investigated in a background of disorder exchange distributions. By means of both real space decimation procedures and numerical diagonalizations in XX chains, it is found that for binary disorder the magnetization exhibits wide plateaus at values of 1+2(p-1)/q, where p is the disorder strength. In contrast, no spin gaps are observed in the presence of continuous exchange distributions. We also study the magnetic susceptibility at low magnetic fields.

Journal Article↗
PubMed2000

Semiquantitative reverse transcription-polymerase chain reaction to evaluate the expression patterns of genes involved in the oestrogen pathway.

The increasing number of factors to be taken into account in the oestrogen transcriptional process has created a need to develop a rapid screening method to evaluate their role in physiology and pathology. Molecular biology techniques enable gene expression studies at the mRNA level with small amounts of tissues. We therefore developed a semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) technique using fluorescent oligonucleotides to analyse simultaneously a large panel of interrelated genes involved in the oestrogen transcriptional pathway using a moderately expressed housekeeping gene, the hypoxanthine phosphoribosyltransferase gene (HPRT), as the reference gene. Expression levels of oestrogen receptors (ERalpha, ERbeta), cofactors AIB1, RIP140, SMRT and the Fas-associated protein-tyrosine phophatase-1 (FAP-1) genes were evaluated in breast, endometrial and ovarian cancer cell lines and in three ERalpha-positive and three ERalpha-negative breast cancer tumours. This technique provides a rapid and reliable way to quantitate simultaneously numerous mRNAs of genes involved in the oestrogen pathway from small amounts of tissues.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Neoadjuvant tamoxifen for operable breast cancer: a need for phase III studies?

We conducted a case-control study to analyze the effect of neoadjuvant tamoxifen on steroid receptors and histologic grade and to evaluate the feasibility of phase III studies in operable breast cancer. Between 1987 and 1990, 107 patients without clinical metastases who had had no chemotherapy preoperatively, were treated preoperatively with 20 mg/day of tamoxifen for 3 weeks. Of them, 92 were matched with controls for age at diagnosis, year of diagnosis, presence or absence of lymph node involvement, and preoperative radiotherapy. The percentage of ER1 tumors (P = .03) and the mean and median ER levels (P<.001 for both) were lower in the tamoxifen group than in the control group. In six patients analyzed longitudinally, the mean ER decreased from 52 to 19 fmol/mg protein. The difference in relapse-free survival between the two groups was not significant (mean follow-up 87 months). This study suggests a decrease in ER content in patients treated with neoadjuvant tamoxifen. This change may thus be taken into account when ER determination is performed after tamoxifen therapy is started. Further randomized trials should determine whether patients with operable breast cancer benefit from neoadjuvant tamoxifen treatment.

Antineoplastic Agents, Hormonal↗
PubMed2000

[Non-genomic steroid effects: estrogen action revisited].

Estrogen receptors (ERs) are members of the nuclear receptor superfamily and act classically as transcription factors. However, it has been noted that estrogens could have early cell effects (within a few minutes) that cannot be explained by transcription activation and protein synthesis. There is now an emerging body of evidence that estrogens, like many other steroids, may cause rapid activation of signal transduction pathways. These non-genomic effects involve common second messengers, such as increased intracellular calcium levels phosphoinositide turnover or cAMP accumulation. Recent studies have also shown that estrogens can stimulate the MAP kinase signaling pathway through ERs. These effects have been observed in various estrogen target cells, including endothelial cells, osteoblasts, neurons and breast cancer cells. The ER membrane signaling pathway is thus a new component that could be taken into account to understand the complex modulation of estrogen effects in specific tissues. It could also be a new therapeutic target for the treatment of neurodegenerative, cardiovascular or breast cancer diseases.

Animals↗
PubMed1999

Time at surgery during menstrual cycle and menopause affects pS2 but not cathepsin D levels in breast cancer.

Many studies have addressed the clinical value of pS2 as a marker of hormone responsiveness and of cathepsin D (Cath D) as a prognostic factor in breast cancer. Because pS2 and Cath D are both oestrogen induced in human breast cancer cell lines, we studied the influence of the menstrual cycle phase and menopausal status at the time of surgery on the levels of these proteins in breast cancer. A population of 1750 patients with breast cancer, including 339 women in menstrual cycle, was analysed. Tumoral Cath D and pS2 were measured by radioimmunoassay. Serum oestradiol (E2), progesterone (Pg), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels at the day of surgery were used to define the hormonal phase in premenopausal women. There was a trend towards a higher mean pS2 level in the follicular phase compared with the luteal phase (17 ng mg(-1) and 11 ng mg(-1) respectively, P = 0.09). Mean pS2 was lower in menopausal patients than in women with cycle (8 ng mg(-1) and 14 ng mg(-1) respectively, P = 0.0001). No differences in mean Cath D level were observed between the different phases of the menstrual cycle, or between pre- and post-menopausal women. In the overall population, pS2 was slightly positively associated with E2 and Pg levels and negatively associated with FSH and LH, probably reflecting the link between pS2 and menopausal status. In premenopausal women, no association was found between pS2 and E2, Pg, FSH or LH levels. There were no correlations between Cath D level and circulating hormone levels in the overall population. However, in the subgroup of premenopausal women with ER-positive (ER+) tumours, E2 was slightly associated with both pS2 and Cath D, consistent with oestrogen induction of these proteins in ER+ breast cancer cell lines. There are changes in pS2 level in breast cancer throughout the menstrual cycle and menopause. This suggests that the choice of the pS2 cut-off level should take the hormonal status at the time of surgery into account. In contrast, the level of Cath D is unrelated to the menstrual cycle and menopausal status.

Breast Neoplasms↗