Crosstalk between steroid receptors and the c-Src-receptor tyrosine kinase pathways: implications for cell proliferation

Shupnik, Margaret A.

doi:10.1038/sj.onc.1208076

Cited by 191 publications

(144 citation statements)

References 125 publications

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“…It is tempting to speculate that regulation of BACE and APP internalization by RTK activation is critical for Aβ production, and that an aberration of such regulation might contribute to the senile plaque formation. c-Src is an integral component of the signal transduction apparatus employed by RTKs [61] and plays pivotal roles in the internalization of various membrane proteins such as β2AR, ROMK-1, AT1R, and EGFR. Consistent with these reports, we demonstrated that RTK-induced BACE internalization and subsequent Aβ production also depended on the activity of c-Src.…”

Section: Discussionmentioning

confidence: 99%

Receptor tyrosine kinases positively regulate BACE activity and Amyloid-β production through enhancing BACE internalization

et al. 2007

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Amyloid-β (Aβ) peptide, the primary constituent of senile plaques in Alzheimer's disease (AD), is generated by β-secretase-and γ-secretase-mediated sequential proteolysis of the amyloid precursor protein (APP). The aspartic protease, β -site APP cleavage enzyme (BACE), has been identified as the main β-secretase in brain but the regulation of its activity is largely unclear. Here, we demonstrate that both BACE activity and subsequent Aβ production are enhanced after stimulation of receptor tyrosine kinases (RTKs), such as the receptors for epidermal growth factor (EGF) and nerve growth factor (NGF), in cultured cells as well as in mouse hippocampus. Furthermore, stimulation of RTKs also induces BACE internalization into endosomes and Golgi apparatus. This enhancement of BACE activity and Aβ production upon RTK activation could be specifically inhibited by Src family kinase inhibitors and by depletion of endogenous c-Src with RNAi, and could be mimicked by over-expressed c-Src. Moreover, blockage of BACE internalization by a dominant negative form of Rab5 also abolished the enhancement of BACE activity and Aβ production, indicating the requirement of BACE internalization for the enhanced activity. Taken together, our study presents evidence that BACE activity and Aβ production are under the regulation of RTKs and this is achieved via RTK-stimulated BACE internalization, and suggests that an aberration of such regulation might contribute to pathogenic Aβ production.

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Section: Discussionmentioning

confidence: 99%

Receptor tyrosine kinases positively regulate BACE activity and Amyloid-β production through enhancing BACE internalization

et al. 2007

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“…HER2 overexpression is a poor prognostic indicator in breast cancer and has been implicated in TAM resistance [8][9][10]. In general, HER2 gene amplification and protein overexpression are inversely correlated with expression of ERα, or with ERα and ERβ together [63,90,[94][95][96][97].…”

Section: Coexpression Of Erβ With Erα and Other Potential Markers In mentioning

confidence: 99%

“…Numerous clinical studies have shown that ERα expression predicts a greater likelihood of response to TAM therapy and is associated with increased survival in patients treated with adjuvant TAM [2,7,82], but only about 40-80% of patients with ERα+ tumors initially respond to TAM, and many of these patients eventually become resistant [7][8][9][10]. A recent review notes that nine of ten retrospective studies support the idea that increased expression of ERβ protein in ERα+/ERβ+ breast tumors is associated with higher likelihood of response to endocrine therapy [79].…”

Section: Clinical Correlations Between Erβ Expression and Response Tomentioning

confidence: 99%

“…Because the PR gene is ER-regulated, its expression has been interpreted to indicate a functioning ER and, therefore, an E2-responsive tumor. Alternative growth factor-sensitive pathways, identified by the presence of the EGF receptor family member HER2, are also associated with poor response to endocrine therapy and may cause decreased PR expression [8][9][10]. The discovery in the mid 1990's that there are two subtypes of ER, with different expression profiles in normal and malignant tissues, opened the door to the possibility that ER+ breast tumors might be even more heterogeneous than originally supposed [1].…”

Section: Introductionmentioning

confidence: 99%

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ERβ in breast cancer—Onlooker, passive player, or active protector?

2008

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The role of estrogen exposure in breast cancer risk is well-documented, and both estrogen synthesis and actions through the estrogen receptor (ER) have been targeted by therapies to control hormonedependent breast cancer. The discovery of a second ER form and its therapeutic implications sparked great interest. Both the original ERα and the more recently identified ERβ subtypes bind and respond similarly to many physiological and pharmacological ligands. However, differences in phytoestrogen binding have been noted, and subtype-specific ligands have been developed. Cell-based assays show that ERβ and its variants are generally less active on gene transcription than ERα, and may influence ERα activity; however, both gene-and cell-specific responses occur, and nongenomic activities are less well explored. Specific ligands, and methods to disrupt or eliminate receptor subtype expression in animal and cell models, demonstrate that the ERs have both overlapping and distinct biological functions. Overall, in cell-based studies, ERα appears to play a predominant role in cell proliferation, and ERβ is suggested to be antiproliferative.The potential for distinct populations of breast tumors to be identified based on ER subtype expression, and to exhibit distinct clinical behaviors, is of greatest interest. Several studies suggest that the majority of ER-positive tumors contain both subtypes, but that some tumors contain only ERβ and may have distinct clinical behaviors and responses. Expression of ERβ together with ERα favors positive responses to endocrine therapy in most studies, and additional studies to determine if the addition of ERβ to ERα as a tumor marker is of clinical benefit are warranted. In contrast, the positive association between ERβ and HER2 expression in high-grade ERα-negative breast cancer does not favor positive responses to endocrine therapy. Expression of ERβ in specific clinical subpopulations, and the potential for therapies targeting ERβ specifically, is discussed.

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“…Aberrant expression and activation of src-family kinases have been implicated in a number of human malignancies but thus far they have not proven to be effective clinical targets [12][13]. Despite this, molecular studies continue to show src to play a potential role in clinically important pathways in breast cancer including the steroid and peptide hormone signaling pathways [14][15].…”

Section: Introductionmentioning

confidence: 99%

Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/“triple-negative” breast cancer cell lines growing in vitro

Finn

Dering

Ginther

et al. 2007

Breast Cancer Res Treat

367

288

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Dasatinib is an orally active small molecule kinase inhibitor of both the src and abl proteins. To evaluate the potential role of dasatinib in breast cancer we used 39 human breast cancer cell lines that have been molecular profiled using Agilent Microarrays. They represent both luminal and basal breast cancer subtypes based on the relative gene expression of cytokeratin (CK) 8/CK18 and CK5/CK17, respectively, and those that have undergone an epithelial-tomesenchymal transition (post-EMT) based on their expression of vimentin and the loss of CKs. When treated with 1 lM dasatinib in vitro 8 of them were highly sensitive (>60% growth inhibition), 10 of them were moderately sensitive (40-59% growth inhibition), and 21 were resistant to dasatinib. A highly significant relationship between breast cancer subtype and sensitivity to dasatinib was observed (v 2 = 9.66 and P = 0.008). Specifically, basal-type and post-EMT breast cancer cell lines were most sensitive to growth inhibition by dasatinib. In an attempt to identify potential predictive markers of dasatinib response other than breast cancer subtype we analyzed the baseline gene expression profiles for differentially expressed genes. We identified a set of three biologically relevant genes whose elevated expression is associated with dasatinib inhibition including moesin, caveolin-1, and yes-associated protein-1 with a sensitivity and specificity of 88 and 86%, respectively. Importantly, these data provide scientific rationale for the clinical development of dasatinib in the treatment of women with ''triplenegative'' breast cancer, a subtype that is categorized as being aggressive and lacking effective treatments (i.e. hormonal manipulation or trastuzumab).

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Crosstalk between steroid receptors and the c-Src-receptor tyrosine kinase pathways: implications for cell proliferation

Cited by 191 publications

References 125 publications

Receptor tyrosine kinases positively regulate BACE activity and Amyloid-β production through enhancing BACE internalization

Receptor tyrosine kinases positively regulate BACE activity and Amyloid-β production through enhancing BACE internalization

ERβ in breast cancer—Onlooker, passive player, or active protector?

Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/“triple-negative” breast cancer cell lines growing in vitro

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