Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1140680 (ovarian cancer)
 28,141 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ovarian cancers have a high ability to invade the peritoneal cavity and some are stimulated by estrogens. In an attempt to understand the mode of action of estrogens on these cancer cells and to develop new markers, we have characterized estrogen-regulated proteins. This study was aimed at identifying a protein secreted by ovarian cancer cells whose level was increased by estradiol [Galtier-Dereure, F., Capony, F., Maudelonde, T. & Rochefort, H. (1992) J. Clin. Endocrinol. Metab. 75, 1497-1502]. By using microprotein sequencing, the 110-kDa protein was identified as fibulin-1, a protein of the extracellular matrix that binds to fibronectin, laminin, and nidogen. The amount of immunoprecipitated fibulin-1 secreted into the medium and present in the cell extract was increased up to 10-fold by estradiol in three estrogen-responsive ovarian cancer cell lines. By immunohistochemistry fibulin-1 was located in the stroma of several ovarian cancers and cysts. The findings highlight a potential role for fibulin-1 in the spread of ovarian cancer in the peritoneal cavity and/or in distal metastases.
 ...
PMID:Estrogens increase the expression of fibulin-1, an extracellular matrix protein secreted by human ovarian cancer cells. 855 29

In this overview of results from our laboratory, we address the question of the role of estrogens during early steps of metastasis, involving cell invasion through the basement membrane and cell motility. The motility of several estrogen receptor (ER) positive breast (MCF7, T47D) and ovarian (BG-1, SKOV3, PEO4) cancer cell lines was studied using a modified Boyden chamber assay. We observed, in all cases, estradiol induced inhibition of cancer cell invasion and motility. A similar inhibitory effect of estradiol was found when the wild-type ER alpha was stably transfected in the ER-negative MDA-MB231 cells and 3Y1-Ad12 cancer cells. The mechanism of this inhibitory effect is unknown. In ovarian cancer, however, it may involve intermediary proteins such as fibulin-1, an extracellular matrix protein that strongly interacts with fibronectin and which is induced by estrogen and secreted by ovarian cancer cells. We conclude that estrogens in ER-positive breast and ovarian cancers have a dual effect, since they stimulate tumor growth but inhibit invasion and motility. This may be consistent with the good initial prognostic value of ER-positive breast cancers compared to ER negative breast cancers noted in several clinical studies.
 ...
PMID:Estrogen receptor mediated inhibition of cancer cell invasion and motility: an overview. 969 69

This short review presents the current stage of knowledge of our laboratory on the mechanism of action of cathepsin D and estrogens on tumor progression, mostly based on studies of human breast and ovarian cancer cell lines. Cathepsin D (cath-D) overexpression in breast cancer cells is associated with increased risk of metastasis in patients as confirmed by a recent meta-analysis of clinical studies on node negative breast cancer patients. Transfection of a human cDNA cath-D expression vector increases the metastatic potential of a rat tumor cells line when intravenously injected into nude mice. The mechanism of cath-D induced metastasis seems to require maturation of the pro-enzyme, mostly in large acidic compartments identified as phagosomes. Cath-D is mitogenic in different cell types, and different substrates (growth inhibitors, precursors of growth factor etc.) are proposed to mediate this activity. A mitogenic effect of the pro-enzyme on transmembrane receptor is not totally excluded. The mitogenic activity of estrogens in several estrogen receptor positive breast and ovarian cancer cell lines is well established in our and other laboratories. By contrast the role of estrogens during early steps of metastasis, involving cell invasion through the basement membrane and cell motility is more controversial. The motility of several estrogen receptor (ER) positive breast (MCF7, T47D) and ovarian (BG-1, SKOV3, PEO4) cancer cell lines were studied in our laboratory using a modified Boyden chamber assay. We observed, in all cases, estradiol-induced inhibition of cancer cell invasion and motility. A similar inhibitory effect of estradiol was found when the wild-type ER was stably transfected in the ER-negative MDA-MB231 cells and 3Y1-Ad12 cancer cells. The mechanism of this inhibitory effect is unknown. In ovarian cancer, however it may involve intermediary proteins such as fibulin-1, an extracellular matrix protein that strongly interacts with fibronectin and which is induced by estrogen and secreted by ovarian cancer cells. In breast cancer cells other estrogen regulated proteins may be involved. We conclude that estrogens in ER-positive breast and ovarian cancers have a dual effect, since they stimulate tumor growth but inhibit invasion and motility. This may be consistent with the good initial prognostic value of ER-positive breast cancers compared to ER negative breast cancers noted in several clinical studies, and with the better prognosis of breast cancer occurring after a prolonged treatment of menopause by estrogen as described by the collaborative group on hormonal factors in breast cancer.
 ...
PMID:[Estrogens, cathepsin D and metastasis in cancers of the breast and ovary: invasion or proliferation?]. 984 Oct 98

The study of several human estrogen receptor positive breast cancer cell lines has allowed characterization of a number of estrogen-induced proteins (e.g. progesterone receptor, cathepsin D, pS2 and fibulin-1 in ovarian cell lines). In primary tumours, these markers have different prognostic significance for predicting whether the tumour will be hormone responsive (e.g. pS2, estrogen and progesterone receptors) or will develop metastasis (e.g. cathepsin D). Studies of estrogen-regulated genes should also lead to new therapeutic approaches for hormone-resistant cancers. The role of estrogens as mitogens stimulating the growth of breast and ovarian cancer cell lines is well established. By contrast, their action on metastasis appears more ambiguous. Breast cancer cells without estrogen receptor (ER) are generally less differentiated and more aggressive than those containing functional ER. Moreover, the reexpression of ER by transfection in ER-negative cell lines inhibit their metastatic and invasive potential. These results suggest a protective role of ER in tumor progression. Studies of the underlying mechanisms of this effect may open new therapeutical strategies.
 ...
PMID:[Estrogen-induced genes in breast cancer, and their medical importance]. 1046

Fibulin-1 is an extracellular matrix protein induced by estradiol in estrogen receptor (ER) positive ovarian cancer cell lines. Alternative splicing of fibulin-1 mRNA results in four different variants named A, B, C and D that may have distinct biological functions. We studied the relative expression of fibulin-1 mRNA variants and their estrogen regulation in human ovarian cancer cells. In ovarian tissues and cancer cell lines, fibulin-1C and -1D are the predominant forms, whereas fibulin-1A and -1B are weakly expressed. We developed a competitive PCR assay based on coamplification of fibulin-1C and -1D to study the relative expression of these fibulin-1 variants in human ovarian samples. In ovarian cancer cell lines and ovarian cancer samples, there was a marked increase in the fibulin-1C:1D and fibulin-1C:HPRT mRNA ratios as compared to normal ovaries. In the BG1 estrogen receptor positive ovarian cancer cell line, fibulin-1C mRNA was induced by estradiol in a dose- and time-dependent manner. Since others and we have previously shown an increased expression of ERalpha as compared to ERbeta in ovarian cancer cells, we investigated whether ERalpha or ERbeta is involved in this induction. For this aim, MDA-MB-231 breast cancer cell line, which expresses both low basal levels of ERs and fibulin-1, was infected with recombinant ERalpha or ERbeta encoding adenovirus and treated with estradiol. Fibulin-1C was induced by estradiol in ERalpha- but not ERbeta-infected cells, suggesting that fibulin-1C induction is mediated through ERalpha. In ovarian tumors, a trend towards a correlation between fibulin-1C and ERalpha expression levels was noted. In conclusion, this study showed an increased fibulin-1C:-1D mRNA ratio in ovarian cancer cells as compared to normal ovaries. This finding suggests that the C variant may be involved in ovarian carcinogenesis. Fibulin-1C overexpression may thus be a clue for the understanding of a putative role of estrogens in ERalpha promoted ovarian tumor progression.
 ...
PMID:Estrogen induction and overexpression of fibulin-1C mRNA in ovarian cancer cells. 1185 Aug 27

Chemotherapy with carboplatin and paclitaxel is the standard treatment for ovarian cancer patients. Although most patients initially respond to this treatment, few are cured. Resistance to chemotherapy is the major cause of treatment failure. We applied a quantitative proteomic approach based on ICAT/MS/MS technology to analyze tissues harvested at primary debulking surgery before the initiation of combination chemotherapy in order to identify potential naive or intrinsic chemotherapy response proteins in ovarian cancers. We identified 44 proteins that are overexpressed, and 34 proteins that are underexpressed in the chemosensitive tissue compared to the chemoresistant tissue. The overexpressed proteins identified in the chemoresistant tissue include 10 proteins (25.6%) belonging to the extracellular matrix (ECM), including decorin, versican, basigin (CD147), fibulin-1, extracellular matrix protein 1, biglycan, fibronectin 1, dermatopontin, alpha-cardiac actin (smooth muscle actin), and an EGF-containing fibulin-like extracellular matrix protein 1. Interesting proteins identified as overexpressed in the chemosensitive tissue include gamma-catenin (junction plakoglobin) and delta-catenin, tumor suppressor p53-binding protein 1 (53BP1), insulin-like growth factor-binding protein 2 (IGFBP2), proliferating cell nuclear antigen (PCNA), annexin A11, and 53 kDa selenium binding protein 1. Integrative analysis with expression profiling data of eight chemoresistant tissues and 13 chemosensitive tissues revealed that 16 proteins showed consistent changes at both the protein and the RNA levels. These include P53 binding protein 1, catenin delta 1 and plakoglobin, EGF-containing fibulin-like extracellular matrix protein 1 and voltage-dependent anion-selective channel protein 1. Our results suggest that chemotherapy response may be determined by multiple and complex system properties involving extracellular-matrix, cell adhesion and junction proteins.
 ...
PMID:Quantitative proteomics analysis integrated with microarray data reveals that extracellular matrix proteins, catenins, and p53 binding protein 1 are important for chemotherapy response in ovarian cancers. 1942 1