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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increasing evidence supports the hypothesis that "dose" is critical to the clinical outcomes of cytotoxic chemotherapy for patients with breast cancer. Clinical trials continue to investigate whether higher doses of chemotherapy lead to proportionate improvements in the outcomes of patients. Delivery of dose-intensive chemotherapy has been facilitated by technological advancements in supportive care. Improved antiemetics have led to increased patient tolerance of the most acute symptoms of aggressive chemotherapeutic dosing. Chemotherapy-induced myelosuppression may be minimized in a lineage-specific manner by appropriate use of hematopoietic cytokines such as filgrastim (granulocyte colony-stimulating factor), sargramostim (granulocyte-macrophage colony-stimulating factor), and/or epoetin alfa (erythropoietin). However, cumulative myelotoxicity occurs with dose-intensive chemotherapy over multiple cycles despite adjunctive cytokine support. Additionally, no cytokine has yet been demonstrated to support platelet production to any clinically significant degree although several regulators of platelet production (such as thrombopoietin, IL-6, and IL-11) are in clinical trials. Many cytokines can induce the mobilization of hematopoietic progenitor and stem cells from the bone marrow into the circulating blood pool, where these cells may be harvested. Clinical use of these cytokine-mobilized peripheral blood progenitor cells (also known as PBPCs or, commonly, as blood stem cells) has documented the effectiveness of these cells to reconstitute multilineage blood production following very high-dose chemotherapy. The ease with which PBPCs can be collected and their reproducible clinical effectiveness to support patients through intensive treatment protocols have led to a virtual elimination of bone marrow as the source of cellular support for myeloablative chemotherapy in many transplant centers. Novel investigative approaches are also possible with PBPCs. In this review, the historical background of PBPCs is summarized, and the potential benefits (including economic advantages) of PBPCs to support dose-intensive chemotherapy for treating breast cancer are discussed. While dose intensification of breast cancer chemotherapy to the degree requiring PBPC support remains controversial and, in most centers, investigational, there is no doubt that PBPCs are an effective adjunct to the hematopoietic support of patients undergoing transplant-level cytotoxic treatments. Further study will undoubtedly lead to increased use of PBPCs in novel treatments for patients with breast cancer and other solid tumors.
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PMID:The emergence of peripheral blood progenitor cells to support intensive chemotherapy for patients with breast cancer. 872 88

The expression of transcripts of cytokines of the interleukin-6 (IL-6) family has been examined in human breast tumors, breast cancer cell lines, and adipose stromal cells, by means of reverse transcription polymerase chain reaction amplification. Of the six breast tumor samples examined, all expressed transcripts encoding IL-6 and Leukemia Inhibitory Factor (LIF). Four of the samples also expressed transcripts for oncostatin M (OSM) and IL-11, and three expressed the IL-6 receptor. Adipose stromal cells expressed IL-6, IL-11 and LIF, but not the IL-6 receptor, consistent with previous conclusions that IL-6 activity in these cells required addition of IL-6 soluble receptor. In the case of T47D cells, expression of IL-11 protein was confirmed by immunotitration. Moreover, in these cells, expression of IL-11 transcripts was induced 3-fold by addition of estradiol to the culture medium. These results add credence to our previous proposal that breast cancer development is regulated in part by local autocrine and paracrine mechanisms via epithelial/mesenchymal interactions, in which estrogen produced by stromal cells surrounding the tumor acts to stimulate the production of growth factors and cytokines by the tumor cells. Some of these may act to stimulate further the growth and development of the tumor, while these or other factors may act on the surrounding mesenchymal cells in a paracrine fashion to stimulate aromatase expression in the presence of glucocorticoids. Thus, a positive feedback loop is established which leads to the development and growth of the tumor.
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PMID:Expression of transcripts of interleukin-6 and related cytokines by human breast tumors, breast cancer cells, and adipose stromal cells. 873 8

In situ oestrogen synthesis makes an important contribution to the high oestrogen concentration found in breast tumours. Cytokines, including interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF alpha), have been shown to regulate aromatase activity in fibroblasts derived from normal and malignant breast tissues. In the present study, the ability of other cytokines in the IL-6 superfamily (IL-11 and oncostatin M) to stimulate aromatase activity has been confirmed. Formation of oestrone via the oestrone sulphatase pathway may be the major route of tumour oestrogen synthesis and in the present study TNF alpha was found to stimulate sulphatase activity in a dose-dependent manner. Human serum albumin was also found to be a potent stimulator of oestrone sulphatase activity. Its stimulatory effect was blocked by basic fibroblast growth factor, but not by several other growth factors tested. Insight into the regulation of oestrogen synthesis in breast tumours should enable the development of novel compounds to inhibit oestrogen synthesis in women with breast cancer.
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PMID:Regulation of aromatase and sulphatase in breast tumour cells. 894 89

We evaluated different culture conditions to obtain a lineage-selected proliferation of clonogenic megakaryocytic progenitors (MP). In low-density (LD) or CD34+ cell cultures, the best results were obtained in serum-free medium in the presence of megakaryocyte growth and development factor, stem cell factor, interleukin-3 (IL-3), IL-6, IL-11, FLT-ligand, and macrophage inflammatory protein-1alpha. In paired studies, expansion of LD cells was less effective than expansion of CD34+ cells, and pre-enrichment of CD34+ cells using negative depletion of lineage-positive cells produced significantly larger quantities of MP than pre-enrichment using positive selection. MP proliferation peaked on day 7 in culture, and an 8- +/- 5-fold expansion of CD34+/CD61+ cells, a 17- +/- 5-fold expansion of colony-forming units-megakaryocytes, and a 58- +/- 14-fold expansion of the total number of CD61+ cells was obtained. In a feasibility clinical study, 10 cancer patients (8 with breast cancer and 2 with non-Hodgkin's lymphoma) undergoing autologous peripheral blood progenitor cell (PBPC) transplant received MP generated ex vivo (range, 1 to 21 x 10(5)/kg CD61 cells) together with unmanipulated PBPC. Eight patients received a single allogeneic platelet transfusion, whereas platelet transfusion support was not needed in 2 of the 4 patients receiving the highest doses of cultured MP. This result compares favorably with a retrospective control group of 14 patients, all requiring platelet transfusion support. Adverse reactions or bacterial contamination of cell cultures have not been observed. In conclusion, MP can be expanded ex vivo and safely administered to autologous transplant recipients. Further clinical trials will indicate the reinfusion schedule able to consistently abrogate the need for allogeneic platelet transfusion support in autologous transplantation.
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PMID:Megakaryocytic progenitors can be generated ex vivo and safely administered to autologous peripheral blood progenitor cell transplant recipients. 910 85

Estrogen biosynthesis in adipose tissue increases with age and obesity, and has been implicated in the development of endometrial cancer and breast cancer. In normal human adipose tissue, expression of the CYP19 gene which encodes aromatase P450, the enzyme responsible for estrogen biosynthesis, is regulated by a distal promoter, namely promoter I.4. Stimulation of expression in adipose stromal cells by members of the type 1 cytokine family, i.e. interleukin (IL)-6, IL-11, leukemia inhibitory factor (LIF) and oncostatin M (OSM), is mediated via a Jak-STAT3 signaling pathway and a GAS element upstream of promoter I.4. In contrast, aromatase expression in breast adipose tissue proximal to tumor is increased three- to four-fold to the utilization of another promoter, namely promoter II, proximal to the translation initiation site. In the present report, we show that prostaglandin (PG) E2 is the most potent factor which stimulates aromatase expression via cyclic AMP and promoter II. PGE2 acts via EP1 and EP2 receptor subtypes to stimulate both the PKC and PKA pathways. The combined stimulation of both of these pathways results in the maximal expression of promoter II-specific CYP19 transcripts. Because PGE2 is a major secretory product both of breast tumor epithelial cells and fibroblasts, as well as of macrophages infiltrating the tumor site, then this could be the mechanism whereby estrogen biosynthesis is stimulated in breast sites adjacent to a tumor, leading in turn to increased growth and development of the tumor itself.
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PMID:Transcriptional regulation of CYP19 gene (aromatase) expression in adipose stromal cells in primary culture. 936 91

Some epidemiological studies have suggested that aspirin could be a chemopreventive agent against breast cancer. We tested the effects of the aspirin metabolite salicylate (SA) on four (Hs578T, MCF-7, MDA-MB-231, and T-47D) breast cancer cell (BCC) lines in vitro. Two features were studied: the proliferation of BCC and their production of the osteolytic cytokines interleukins-6 (IL-6) and -11 (IL-11) since BCC frequently metastasize to bone and induce tumor-induced osteolysis. SA, from 0.5 to 5 mM, caused BCC growth inhibition by up to 70% (IC50 range 2.54 to 4.28 mM). At high concentrations, the drug induced apoptosis only (MDA-MB-231), or both apoptosis and primary necrosis (MCF-7). SA, as well as indomethacin (INDO), reduced the synthesis of IL-6 and -11, at both the protein and mRNA levels, in the two cell lines producing these cytokines (MDA-MB-231 and Hs578T). This latter effect seemed to be mediated by PGE2 since SA and INDO reduced PGE2 levels in MDA-MB-231 and Hs578T cells, PGE2 was not detected in MCF-7 and T-47D cells and exogenous PGE2 increased IL-6 and -11 expression by MDA-MB-231 cells. Collectively, our results suggest that SA could reduce the growth of breast tumors and inhibit to some extent the ability of BCC to induce osteoclast recruitment and osteolysis. These data indicate the need for further epidemiological and experimental studies.
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PMID:The aspirin metabolite salicylate inhibits breast cancer cells growth and their synthesis of the osteolytic cytokines interleukins-6 and -11. 1065 84

The dense layer of fibroblasts that accumulate around malignant breast epithelial cells (i.e., desmoplastic reaction) arises from the breast adipose tissue and provides structural and biochemical support for breast cancer. We report herein a number of epithelial-stromal interactions responsible for desmoplastic reaction in breast cancer using cultured 3T3-L1 murine fibroblasts and human adipose fibroblasts, which can be activated with a mixture of hormones to differentiate to mature adipocytes. Adipocyte differentiation was inhibited by coculturing fibroblasts with various breast cancer cell lines (T47D, MCF-7, SSC202, SSC78, and SSC30) completely or by breast cancer cell conditioned media in a dose-dependent manner; on the other hand, adipocyte differentiation was not inhibited by coculturing with normal human primary mammary epithelial cell conditioned medium. This tumor effect was eliminated using neutralizing antibodies against tumor necrosis factor (TNF)-alpha or interleukin (IL)-11. TNF-alpha and IL-11 levels were 2.5-3 times higher in T47D conditioned medium compared with control medium, and TNF-alpha transcripts were detectable in T47D but not in 3T3-L1 cells in culture, indicating that the malignant epithelial cell is the major site of cytokine production. This was confirmed in vivo in mastectomy specimens, where immunoreactive TNF-alpha and IL-11 were readily detectable in malignant epithelial cells but not in the majority of the surrounding fibroblasts. Adipocyte differentiation is mediated by the expression of a cascade of adipogenic transcription factors, including CCAAT/enhancer binding protein (C/EBP)beta, C/EBPdelta, peroxisome proliferator-activated receptor (PPAR)gamma and C/EBPalpha. C/EBPalpha and PPARgamma are essential for this process. We demonstrated by Northern analysis that exposure of activated 3T3-L1 cells to T47D cell conditioned medium strikingly decreased the levels of PPARgamma and C/EBPalpha transcripts and increased the levels of C/EBPbeta and C/EBPdelta transcripts. In these 3T3-L1 cells, inhibition of differentiation was also confirmed by markedly suppressed levels of aP2 mRNA, which is an adipocyte-specific gene. These in vitro observations were confirmed in sections of human malignant breast tumors, where immunoreactive C/EBPalpha was readily detectable in adipose flbroblasts distant to the tumor but not in intratumoral fibroblasts. Treatment of 3T3-L1 cells with T47D cell conditioned medium or TNF-alpha changed neither the numbers of cells in G0-G1, S, and G2 phases nor the rate of [3H]thymidine incorporation, thus ruling out a proliferative effect of malignant cells on the surrounding fibroblasts. In summary, desmoplastic reaction primarily occurs via the action of cytokines (TNF-alpha and IL-11) secreted by the malignant epithelial cells to inhibit differentiation of adipose fibroblasts to mature adipocytes. This tumor-induced block in adipocyte differentiation is mediated by the selective inhibition of expression of the essential adipogenic transcription factors, i.e., PPARgamma and C/EBPalpha.
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PMID:Tumor necrosis factor alpha and interleukin 11 secreted by malignant breast epithelial cells inhibit adipocyte differentiation by selectively down-regulating CCAAT/enhancer binding protein alpha and peroxisome proliferator-activated receptor gamma: mechanism of desmoplastic reaction. 1128 Jul 94

Breast cancer cells frequently metastasize to the skeleton, where they induce OCL formation and activity, resulting in extensive bone destruction. However, the mechanisms by which breast cancer cells mediate increased osteolysis remain unclear. To elucidate this point, we investigated how 3 human breast cancer cell lines, MDA-MB-231, MDA-MB-435 and MCF-7, induce OCL formation using a murine osteoblast-spleen cell coculture system and compared their effects with a human colorectal cancer cell line, HCT-15; a human lung cancer cell line, HT-1080; and a normal human breast cell line, HME. The breast cancer cell lines supported OCL formation only when osteoblasts were present in spleen cell cocultures, whilst the non-breast cancer cell lines and the normal breast cell line, HME, had no effect. Fractionation of BCCM by ultrafiltration established that osteoclastogenic activity was associated with factors having m.w. >3 kDa. Breast cancer cell lines produced primarily PTHrP, with lesser amounts of IL-6, IL-11 and TNF-alpha. The effect of BCCM on OCL formation in osteoblast-spleen cell cocultures was partially prevented by a neutralising antibody to human PTHrP and completely prevented by a neutralising antibody to either murine IL-11 or the murine IL-11 receptor; neutralising antibodies to human IL-6, IL-11 or TNF-alpha were without effect. BCCM or human PTHrP induced an increase in murine osteoblast IL-11 mRNA and protein production, effects that were prevented in the presence of a neutralising antibody to human PTHrP. The osteoclastogenic activity of IL-11 was mediated by enhancing osteoblast production of PGE(2) effects, which were abrogated by an inhibitor of cyclooxygenase. PGE(2) apparently enhanced OCL formation by downregulating GM-CSF production by spleen cells since recombinant murine GM-CSF inhibited OCL formation and a neutralising antibody to murine GM-CSF blocked these inhibitory effects. We conclude that breast cancer cells induce OCL formation by stimulating osteoblastic production of IL-11. The subsequent release of PGE(2) followed by inhibition of GM-CSF production by cells within the bone microenvironment plays an important part in mediating the effects of breast cancer cells on OCL formation and their resorptive activity.
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PMID:Breast cancer cells induce osteoclast formation by stimulating host IL-11 production and downregulating granulocyte/macrophage colony-stimulating factor. 1499 70

TGF-beta can signal by means of Smad transcription factors, which are quintessential tumor suppressors that inhibit cell proliferation, and by means of Smad-independent mechanisms, which have been implicated in tumor progression. Although Smad mutations disable this tumor-suppressive pathway in certain cancers, breast cancer cells frequently evade the cytostatic action of TGF-beta while retaining Smad function. Through immunohistochemical analysis of human breast cancer bone metastases and functional imaging of the Smad pathway in a mouse xenograft model, we provide evidence for active Smad signaling in human and mouse bone-metastatic lesions. Genetic depletion experiments further demonstrate that Smad4 contributes to the formation of osteolytic bone metastases and is essential for the induction of IL-11, a gene implicated in bone metastasis in this mouse model system. Activator protein-1 is a key participant in Smad-dependent transcriptional activation of IL-11 and its overexpression in bone-metastatic cells. Our findings provide functional evidence for a switch of the Smad pathway, from tumor-suppressor to prometastatic, in the development of breast cancer bone metastasis.
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PMID:Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. 1617 83

In recent decades many advances have occurred in the understanding of the role of cytokines in breast cancer. New signalling pathways of interleukin (IL)-1 family, IL-6, IL-11, IL-18, interferons (IFNs) and interferon regulatory factors 1 (IRF-1) and 2 (IRF-2) have been found within tumour microenvironments and in metastatic sites. Some cytokines (IL-1, IL-6, IL-11, TGFbeta) stimulate while others (IL-12, IL-18, IFNs) inhibit breast cancer proliferation and/or invasion. Similarly, high circulating levels of some cytokines seem to be favourable (soluble IL-2R) while others are unfavourable (IL-1beta, IL-6, IL-8, IL-10, IL-18, gp130) prognostic indicators. So far IL-2, IFNalpha, IFNbeta and occasionally IFNgamma, IL-6, IL-12 have been the cytokines used for anti tumour treatment of advanced breast cancer either to induce or increase hormone sensitivity and/or to stimulate cellular immunity. Disappointing results occurred in most trials; however, two long-term pilot studies suggest that IL-2 and IFNbeta, when used appropriately can have a positive effect on clinical benefit and overall survival of patients with minimal residual disease after chemotherapy or with disseminated disease controlled by conventional endocrine therapy.
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PMID:Cytokines in breast cancer. 1693 Nov 7


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