Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epidermal growth factor (EGF) expresses mitogenic activity by a mechanism that requires the EGF receptor (EGFR). We report that murine embryonic fibroblasts (MEFs) proliferate in response to EGF only when these cells express the urokinase receptor (uPAR). EGFR expression was equivalent in uPAR-/- and uPAR+/+ MEFs. In response to EGF, these cells demonstrated equivalent overall EGFR tyrosine phosphorylation and ERK/MAP kinase activation; however, phosphorylation of Tyr-845 in the EGFR, which has been implicated in cell growth, was substantially decreased in uPAR-/- MEFs. STAT5b activation also was decreased. As Tyr-845 is a c-Src target, we overexpressed c-Src in uPAR-/- MEFs and rescued EGF mitogenic activity. Rescue also was achieved by expressing murine but not human uPAR, suggesting a role for autocrine uPAR cell-signaling. In MDA-MB 231 breast cancer cells, EGF mitogenic activity was blocked by uPAR gene silencing, with antibodies that block uPA-binding to uPAR, and with a synthetic peptide that disrupts uPAR-dependent cell signaling. Again, c-Src overexpression rescued the mitogenic activity of EGF. We conclude that uPAR-dependent cell-signaling may prime cells to proliferate in response to EGF by promoting Tyr-845 phosphorylation and STAT5b activation. The importance of this pathway depends on the c-Src level in the cell.
 ...
PMID:Urokinase receptor primes cells to proliferate in response to epidermal growth factor. 1704 37

Overexpression and/or activity of c-Src non-receptor tyrosine kinase is associated with progression of several human epithelial cancers including breast cancer. c-Src activity in 'pure' ductal carcinoma in situ (DCIS) was measured to assess whether this predicts recurrence and/or correlates with HER2 expression and other clinical parameters. Activated c-Src levels were evaluated in DCIS biopsies from 129 women, with median follow-up at 60 months. High levels of activated c-Src correlated with HER2 positivity, high tumour grade, comedo necrosis and elevated epithelial proliferation. In univariate analysis, high activated c-Src level associated with lower recurrence-free survival at 5 years (P=0.011). Thus, high c-Src activity may identify a subset of DCIS with high risk of recurrence or progression to invasive cancer where therapeutics targeting c-Src may benefit this patient subset.
 ...
PMID:Activated c-SRC in ductal carcinoma in situ correlates with high tumour grade, high proliferation and HER2 positivity. 1706 Sep 31

Progesterone receptor (PR) ligand binding induces rapid and transient (5- to 10-min) activation of cytosolic c-Src-Ras-Erk1/2 mitogen-activated protein kinase (MAPK) signaling that is independent of PR functioning as transcription factors. Here, we have explored the integration of PR-dependent transcription and rapid signaling events in breast cancer cells. PR-B, but not PR-A, induced robust and sustained (6- to 72-h) Erk1/2 activation that was required for elevated cyclin D1 protein but not mRNA levels. Sustained Erk1/2 activation in response to progestins occurred via a novel mechanism distinct from rapid signaling initiated by PR/c-Src interactions and required the PR-B DNA-binding domain (DBD). PR/progestin upregulated epidermal growth factor receptor (EGFR) and Wnt-1. In response to PR-induced Wnt-1 signaling, matrix metalloprotease (MMP)-mediated membrane-proximal shedding of EGFR ligands transactivated EGFR and induced persistent downstream c-Src and Erk1/2 activities. T47D cell anchorage-independent growth was stimulated by progestins and blocked by inhibition of Erk1/2, c-Src, EGFR, or RNA interference of Wnt-1. Similarly, cell growth in soft agar required the PR DBD but was sensitive to disruption of PR/c-Src interactions, suggesting that both PR-B-induced rapid signaling events and nuclear actions contribute to this response. Our discovery that progestins are capable of robust autocrine activation of EGFR and sustained Erk1/2 signaling provides further support for the physiological linkage of growth factor and steroid hormone signaling. PR-B-induced sustained MAPK signaling may provide prosurvival or proliferative advantages to early breast cancer lesions.
 ...
PMID:Progesterone receptors upregulate Wnt-1 to induce epidermal growth factor receptor transactivation and c-Src-dependent sustained activation of Erk1/2 mitogen-activated protein kinase in breast cancer cells. 1707 4

It has long been appreciated that estrogenic signaling contributes to breast cancer progression. c-Src is also required for a number of processes involved in tumor progression and metastasis. We have previously identified the K303R mutant estrogen receptor alpha (ERalpha) that confers hypersensitivity to low levels of estrogen. Because ERalpha and c-Src have been shown to interact in a number of different systems, we wanted to evaluate the role of c-Src kinase in estrogen-stimulated growth and survival of ERalpha-positive breast cancer cells. MCF-7 cells stably expressing the mutant receptor showed increased c-Src kinase activity and c-Src tyrosine phosphorylation when compared with wild-type ERalpha-expressing cells. A c-Src inhibitor, AZD0530, was used to analyze the biological effects of pharmacologically inhibiting c-Src kinase activity. MCF-7 cells showed an anchorage-dependent growth IC50 of 0.47 micromol/L, which was increased 4-fold in the presence of estrogen. In contrast, cells stably expressing the mutant ERalpha had an elevated IC50 that was only increased 1.4-fold by estrogen stimulation. The c-Src inhibitor effectively inhibited the anchorage-independent growth of both of these cells, and estrogen was able to reverse these effects. When cells were treated with suboptimal concentrations of c-Src inhibitor and tamoxifen, synergistic inhibition was observed, suggesting a cooperative interaction between c-Src and ERalpha. These data clearly show an important role for ERalpha and estrogen signaling in c-Src-mediated breast cancer cell growth and survival. Here, we show that c-Src inhibition is blocked by estrogen signaling; thus, the therapeutic use of c-Src inhibitors may require inhibition of ERalpha in estrogen-dependent breast cancer.
 ...
PMID:Cooperative action of tamoxifen and c-Src inhibition in preventing the growth of estrogen receptor-positive human breast cancer cells. 1717 5

Overexpression and/or gene amplification of c-Src and members of the epidermal growth factor receptor (EGFR/ErbB) family have been implicated in the pathogenesis of breast cancer. Although members of the EGFR family are known to form heterocomplexes with one another, c-Src has also been shown to physically interact with members of this family in breast cancer cell lines and tumors. This paper investigates the role of c-Src in modulating the physical and functional interaction between ErbB2 and ErbB3, two family members that preferentially associate with one another and together exhibit high oncogenic potential. We show that overexpressed wild-type c-Src enhances heterocomplex formation of ErbB2 and ErbB3 that results in increased basal and/or heregulin-induced activation of receptors, and their downstream intracellular effectors. Expression of a kinase-inactive form of c-Src (K(-) c-Src) or pharmacological inhibition of c-Src by PP2 negatively affects these events. Furthermore, cellular motility and anchorage-independent growth promoted by the ErbB2/ErbB3 heterocomplex are dependent upon c-Src, as demonstrated by the effects of K(-) c-Src overexpression or treatment with PP2. In contrast to previous studies that defined a role for c-Src downstream of ErbB2/ErbB3, the current work suggests an upstream mechanism, whereby c-Src enhances ErbB2/ErbB3 signaling and biological functions by positively modulating the association between ErbB2 and ErbB3.
 ...
PMID:c-Src modulates ErbB2 and ErbB3 heterocomplex formation and function. 1717 75

The therapeutic benefit of tamoxifen in patients with hormone-dependent breast cancer is limited by acquired resistance to this drug. To investigate the biological alterations responsible for tamoxifen resistance, an in vitro model was established. After 6-month continuous exposure to tamoxifen (10(-7) mol/L), growth of MCF-7 breast cancer cells was no longer inhibited by this antiestrogen. Although there was no significant increase in the basal levels of activated mitogen-activated protein kinase (MAPK), tamoxifen-resistant (TAM-R) cells exhibited enhanced sensitivity to epidermal growth factor (EGF) and estradiol stimulated activation of MAPK. Tamoxifen elicited rapid phosphorylation of MAPK, in contrast to its antagonistic activity in control cells. Blockade of the EGF receptor (EGFR)/MAPK pathway caused more dramatic inhibition of growth of TAM-R cells than the control cells. An increased amount of estrogen receptor alpha (ERalpha) was coimmunoprecipitated with EGFR from TAM-R cells although the total levels of these receptors were not increased. Notably, ERalpha seemed to redistribute to extranuclear sites in TAM-R cells. Increased ERalpha immunoreactivity in the cytoplasm and plasma membrane of TAM-R cells was shown by fluorescent microscopy and by Western analysis of isolated cellular fractions. In TAM-R cells, an increased amount of c-Src was coprecipitated with EGFR or ERalpha. Blockade of c-Src activity resulted in redistribution of ERalpha back to the nucleus and in reduction of its interaction with EGFR. Prolonged blockade of c-Src activity restored sensitivity of TAM-R cells to tamoxifen. Our results suggest that enhanced nongenomic function of ERalpha via cooperation with the EGFR pathway is one of the mechanisms responsible for acquired tamoxifen resistance.
 ...
PMID:Long-term treatment with tamoxifen facilitates translocation of estrogen receptor alpha out of the nucleus and enhances its interaction with EGFR in MCF-7 breast cancer cells. 1728 73

The signaling pathways that are critical to the development and growth of breast cancer include those activated downstream of the estrogen receptor (ER) and the human epidermal growth factor receptor family. Many of these pathways, including the signal transducer and activator of transcription pathway, are common to both. The well-described genomic actions of ER involve its role as a transcription factor, either by binding directly to DNA through estrogen response elements, or by tethering to DNA through interaction with other proteins. Nongenomic signaling by the ER involves interaction with membrane-associated signaling proteins such as the c-Src tyrosine kinase and adapter proteins p130Cas and moderator of nongenomic activity of ER. Interactions with the signal transducer and activator of transcription pathway are important in both ER signaling pathways and are critical for estrogen-induced proliferation and tumorigenesis. These mechanisms of signaling cross talk and their role in resistance to antiestrogen therapies are discussed.
 ...
PMID:Integration of steroid and growth factor pathways in breast cancer: focus on signal transducers and activators of transcription and their potential role in resistance. 1745 97

Epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases, is overexpressed in as many as 60% cases of breast and other cancers. EGFR overexpression is a characteristic of highly aggressive molecular subtypes of breast cancer with basal-like and BRCA1 mutant phenotypes distinct from ErbB2-overexpressing breast cancers. Yet, EGFR is substantially weaker compared with ErbB2 in promoting the oncogenic transformation of nontumorigenic human mammary epithelial cells (human MEC), suggesting a role for cooperating oncogenes. Here, we have modeled the co-overexpression of EGFR and a biologically and clinically relevant potential modifier c-Src in two distinct immortal but nontumorigenic human MECs. Using a combination of morphologic analysis and confocal imaging of polarity markers in three-dimensional Matrigel culture together with functional analyses of early oncogenic traits, we show for the first time that EGFR and c-Src co-overexpression but not EGFR or c-Src overexpression alone unleashes an oncogenic signaling program that leads to hyperproliferation and loss of polarity in three-dimensional acinar cultures, marked enhancement of migratory and invasive behavior, and anchorage-independent growth. Our results establish that EGFR overexpression in an appropriate context (modeled here using c-Src overexpression) can initiate oncogenic transformation of nontumorigenic human MECs and provide a suitable in vitro model to interrogate human breast cancer-relevant oncogenic signaling pathways initiated by overexpressed EGFR and to identify modifiers of EGFR-mediated breast oncogenesis.
 ...
PMID:Modeling breast cancer-associated c-Src and EGFR overexpression in human MECs: c-Src and EGFR cooperatively promote aberrant three-dimensional acinar structure and invasive behavior. 1748 27

Proline-, glutamic acid-, leucine-rich protein 1 (PELP1), a novel nuclear receptor coactivator, and its expression is deregulated in hormone-dependent cancers, including those of the breast, endometrium, and ovary. PELP1 interacts with estrogen receptor and modulates its genomic and nongenomic functions. In this study, we examined whether PELP1 functions as an oncogene. The overexpression of PELP1 in fibroblasts and epithelial model cells resulted in cellular transformation. PELP1 also enhanced the transformation potential of c-Src kinase in focus formation assays, and PELP1 overexpression potentiated estradiol-mediated cell migratory potential and anchorage-independent growth. Using PELP1-small interfering RNA, we provided evidence that endogenous PELP1 plays an essential role in E2-mediated anchorage-independent growth, cell migration, and cytoskeletal changes. When compared with control vector transfectants, breast cancer cells stably overexpressing PELP1 showed a rapid tumor growth in xenograft studies. Immunohistochemical analysis of PELP1 expression using a tumor progression array of 252 breast carcinomas and normal breast tissue specimens revealed that PELP1 expression is deregulated to a greater degree in higher grade node-positive invasive tumors than in normal breast tissue or ductal carcinoma in situ. Our data suggest that PELP1 is a potential oncogene, that its expression is deregulated during cancer progression, and that PELP1 may play a role in oncogenesis.
 ...
PMID:Oncogenic potential of the nuclear receptor coregulator proline-, glutamic acid-, leucine-rich protein 1/modulator of the nongenomic actions of the estrogen receptor. 1754 33

The discovery that the hop constituent 8-prenylnaringenin (8PN) shows potent estrogenic activity, higher than that of the known phytoestrogens coumestrol, genistein and daidzein, has spurred an intense activity aimed at elucidating its biological profile and its dietary relevance connected with the consumption of beer. We have investigated if 8PN can induce signal transduction pathways via rapid estrogen receptor (ER) activation. Under conditions of estrogen-dependent growth, treatment of MCF-7 human breast cancer cells with 8PN induced a rapid and transient activation of the MAP kinase Erk-1 and Erk-2, with kinetics similar to those induced by 17beta-estradiol (E2). 8PN could trigger the MAP kinase pathway via dual c-Src kinase activation and association with ERalpha. Co-treatment with the ER antagonist ICI 182,780 blocked each step of this transduction pathway, confirming its ER dependence. However, and in striking contrast with E2, 8PN could not induce the PI3K/Akt pathway, resulting in altered kinetics and levels of cyclin D1 expression. In accordance with these observations, flow cytometric and biochemical analysis showed that 8PN inhibited cell cycle progression and induced apoptosis in MCF-7 cells. Interference with an ER associated PI3K pathway is proposed as a possible mechanism underlying the inhibition of survival and proliferation of estrogen responsive cells by 8PN. Taken together, our finding show that 8PN is an interesting new chemotype to explore the biology of ERs.
 ...
PMID:8-Prenylnaringenin, inhibits estrogen receptor-alpha mediated cell growth and induces apoptosis in MCF-7 breast cancer cells. 1768 52


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>