Breast disease. Introduction.
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Journal Article↗
Biomedical subjects
Douglas Yee
Publications and source records attributed to Douglas Yee.
Insulin-like growth factor binding protein-1 (IGFBP-1) inhibits breast cancer cell motility.
The breast cancer malignant phenotype is regulated by steroid hormones and peptide growth factors. We have shown previously that insulin-like growth factor-I (IGF-I) stimulates cell motility in a metastatic cell line, MDA-231BO. In this study, we show that neutralization of IGF action by a type I IGF receptor (IGFR1) blocking antibody or neutralization of IGF-I by IGFBP-1 reduced cell motility. However, in addition to inhibiting IGF effects, IGFBP-1 also diminished basal motility. Because IGFBP-1 contains a RGD motif important in binding of fibronectin to its alpha 5 beta 1 integrin receptor, we examined the effect of inhibiting integrin function on cell motility. As expected, disruption of fibronectin-integrin interactions interrupted basal motility in MDA-231BO cells. In addition, disruption of integrin function by an alpha 5 beta 1 blocking peptide also inhibited IGF stimulation of cell motility. To determine whether integrin function could interfere with IGF signaling, we used an alpha 5 beta 1 blocking peptide to show that in MDA-231BO cells integrin occupancy appeared necessary for phosphorylation of insulin receptor substrate-2 but not for IGFR1 activation. We conclude that IGFR1 and integrin action are linked in these breast cancer cells as disruption of integrin binding to its receptor influences IGF signaling pathways. Moreover, IGFBP-1 could have dual effects on cancer cell motility by disrupting both receptor systems.
Antibodies↗
How does the estrogen receptor work?
In breast cancer, interruption of estrogen receptor (ER)-alpha function is an effective therapeutic strategy. Despite the clinical benefit of interruption of ER-alpha function, the precise biological action of ER-alpha in breast tumors is not completely understood. Results of a recent study show that ER-alpha promotes growth of breast cancer cells by targeting expression of signaling components of the insulin-like growth factor system. Intriguingly, the authors of this study raise the possibility that unliganded ER-alpha itself may affect gene expression and breast cancer biology, and they suggest a potential mechanism for ER-alpha to stimulate proliferation in breast cancer.
Breast Neoplasms↗
Eliminating spurious lipid sidebands in 1H MRS of breast lesions.
Detecting metabolites in breast lesions by in vivo (1)H MR spectroscopy can be difficult due to the abundance of mobile lipids in the breast which can produce spurious sidebands that interfere with the metabolite signals. Two-dimensional J-resolved spectroscopy has been demonstrated in the brain as a means to eliminate these artifacts from a large water signal; coherent sidebands are resolved at their natural frequencies, leaving the noncoupled metabolite resonances in the zero-frequency trace of the 2D spectrum. This work demonstrates that using the zero-frequency trace-or equivalently the average of spectra acquired with different echo times-can be used to separate noncoupled metabolite signals from the lipid-induced sidebands. This technique is demonstrated with simulations, phantom studies, and in several breast lesions. Compared to the conventional approach using a single echo time, echo time averaging provides increased sensitivity for the study of small and irregularly shaped lesions.
Artifacts↗
The insulin-like growth factor system as a treatment target in breast cancer.
Advances in breast cancer treatment have come from the recognition that pathways relevant to cancer cell biology could be identified and targeted. There is abundant in vitro, animal model, and epidemiologic evidence to suggest that the insulin-like growth factors (IGFs) play a role in regulating the malignant phenotype in breast cancer. Insulin-like growth factor action has been implicated in malignant transformation, cellular proliferation, protection from apoptosis, and metastasis. Because IGFs interact with specific cell surface receptors to affect intracellular signaling pathways, blockade of receptor activation could be a successful method to interrupt IGF-driven processes. In contrast to other transmembrane growth factor receptors, the IGF receptor requires activation by ligand. Thus, neutralization of ligand by a "target decoy" could be a useful method to inhibit IGF action. Use of an IGF-binding protein to inhibit activation of IGF receptors will be discussed.
Breast Neoplasms↗
Effects of a 9-month strength training intervention on insulin, insulin-like growth factor (IGF)-I, IGF-binding protein (IGFBP)-1, and IGFBP-3 in 30-50-year-old women.
We assessed the effects of twice weekly strength training on several proposed risk factors for breast and colon cancer: body fat, waist circumference, fasting insulin, fasting glucose, insulin-like growth factor I (IGF-I), and several IGF-binding proteins. Fifty-four healthy women, 30-50 years old, were randomized to no-contact control or treatment: 15 weeks of supervised strength training followed by 6 months of unsupervised training. Fifteen-week changes included reductions in percentage of body fat, fasting insulin, fasting glucose, and IGF-I that were larger in the treatment than control participants (treatment versus control mean +/- SE: % body fat -1.97 +/- 0.42 versus -0.43 +/- 0.40, P = 0.01; insulin (uU/ml) -0.29 +/- 0.35 versus 0.81 +/- 0.38, P = 0.055; glucose (mg/dl) -1.92 +/- 1.27 versus 1.21 +/- 1.36, P = 0.13; and IGF-I (ng/ml) -30.47 +/- 9.75 versus 5.86 +/- 10.44, P = 0.02). There was no treatment effect on IGF-binding proteins 1 and 3 or either of two surrogate measures of free IGF-I. By 39 weeks changes in percentages of body fat were largely maintained; IGF-I returned to baseline levels in the treatment group but remained 15% lower in treatment compared with control participants. Strength training produced favorable changes in several proposed cancer risk factors. The importance of these changes to long-term cancer prognosis, diagnosis, and/or recurrence remains to be determined.
Adult↗
STAT6 mediates interleukin-4 growth inhibition in human breast cancer cells.
In addition to acting as a hematopoietic growth factor, interleukin-4 (IL-4) inhibits growth of some transformed cells in vitro and in vivo. In this study, we show that insulin receptor substrate (IRS)-1, IRS-2, and signal transducer and activator of transcription 6 (STAT6) are phosphorylated following IL-4 treatment in MCF-7 breast cancer cells. STAT6 DNA binding is enhanced by IL-4 treatment. STAT6 activation occurs even after IRS-1 depletion, suggesting the two pathways are independent. To examine the role of STAT6 in IL-4-mediated growth inhibition and apoptosis, a full-length STAT6 cDNA was transfected into MCF-7 cells. Transient overexpression of STAT6 resulted in both cytoplasmic and nuclear expression of the protein, increased DNA binding in response to IL-4, and increased transactivation of an IL-4 responsive promoter. In STAT6-transfected cells, basal proliferation was reduced whereas apoptosis was increased. Finally, stable expression of STAT6 resulted in reduced foci formation compared to vector-transfected cells alone. These results suggest STAT6 is required for IL-4-mediated growth inhibition and induction of apoptosis in human breast cancer cells.
Adenocarcinoma↗