The role of SRC-3 in human breast cancer

Gojiš, Ondřej; Rudraraju, Bharath; Gudi, Mihir; Hogben, Katy; Sousha, Sami; Coombes, R. Charles; Cleator, Susan; Palmieri, Carlo

doi:10.1038/nrclinonc.2009.219

Cited by 51 publications

(39 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SRC is a proto-oncogene encoding a non-receptor tyrosine kinase, similar to the v-Src gene of the Rous sarcoma virus (14), which was initially discovered by Bishop and Varmus (15). The Src protein is formed of seven functional regions: i) N-terminal Src homology domain 4 (SH4) containing a myristic acid moiety, essential for its localization to the inner surface of the cell membrane; ii) a unique domain providing functional specificity to each member of the Src family; iii) SH3 domain, which binds proline-rich sequences to mediate intra-and intermolecular interactions; iv) SH2 domain, which binds phosphorylated tyrosine residues on Src and other proteins; v) a catalytic domain (SH1); and vi) C-terminal tail containing negative-regulatory Tyr530 (in humans) (16)(17)(18) (Fig. 1).…”

Section: Srcmentioning

confidence: 99%

The importance of Src signaling in sarcoma

et al. 2015

View full text Add to dashboard Cite

Abstract. Src is a tyrosine kinase that is of significance in tumor biology. The present review focuses on Src, its molecular structure, and role in cancer, in addition to its expression and function in sarcoma. In addition, the feasibility of Src as a potential drug target for the treatment of sarcoma is also discussed. Previous studies have suggested that Src has essential functions in cell proliferation, apoptosis, invasion, metastasis and the tumor microenvironment. Thus, it may be a potential target for cancer therapy. Src has been found to enhance proliferation, reduce apoptosis and promote metastasis in certain subtypes of sarcoma, including osteosarcoma, chondrosarcoma and Ewing's sarcoma. Furthermore, a number of novel effective therapeutic agents, such as SI-83, which target Src have been investigated in vitro and in vivo. Bosutinib and dasatinib, which inhibit Src, have been approved by the U.S. Food and Drug Administration for the treatment of chronic myelogenous leukemia. In addition, vandetanib is approved for the treatment of medullary thyroid cancer. Furthermore, the Src inhibitor, saracatinib, is currently in clinical trials for the treatment of a variety of solid tumors, including breast and lung cancers. Thus, Src is considered to be an important factor in sarcoma progression and may present a novel clinical therapeutic target. This review demonstrates the importance and clinical relevance of Src in sarcoma, and discusses a number of small molecular inhibitors of src kinase, such as dasatinib and sarcatinib, which are currently in clinical trials for the treatment of sarcoma patients.

show abstract

Section: Srcmentioning

confidence: 99%

The importance of Src signaling in sarcoma

et al. 2015

View full text Add to dashboard Cite

show abstract

“…SRC3 was originally identified as a gene mapping to a region of chromosome 20 (20q12-13), which is frequently amplified in breast cancer and was shown to be amplified in 10% of breast cancers (7). SRC3 mRNA levels are significantly higher in breast cancer as compared with normal mammary tissue (8,9) and SRC3 protein levels are elevated in 16% to 83% (depending on the study) of human breast tumors (10).…”

Section: Introductionmentioning

confidence: 99%

SRC3 Phosphorylation at Serine 543 Is a Positive Independent Prognostic Factor in ER-Positive Breast Cancer

Zwart

Flach

Abdel-Fatah

et al. 2016

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Purpose: The steroid receptor coactivator SRC3 is essential for the transcriptional activity of estrogen receptor a (ERa). SRC3 is sufficient to cause mammary tumorigenesis, and has also been implicated in endocrine resistance. SRC3 is posttranslationally modified by phosphorylation, but these events have not been investigated with regard to functionality or disease association. Here, we investigate the spatial selectivity of SRC3-pS543/DNA binding over the human genome and its expression in primary human breast cancer in relation with outcome.Experimental Design: Chromatin immunoprecipitation, coupled with sequencing, was used to determine the chromatin binding patterns of SRC3-pS543 in the breast cancer cell line MCF7 and two untreated primary breast cancers. IHC was used to assess the expression of SRC3 and SRC3-pS543 in 1,650 primary breast cancers. The relationship between the expression of SRC3 and SRC3-pS543, disease-free survival (DFS), and breast cancer specific survival (BCSS) was assessed.Results: Although total SRC3 is selectively found at enhancer regions, SRC3-pS543 is recruited to promoters of ERa responsive genes, both in the MCF7 cell line and primary breast tumor specimens. SRC3-pS543 was associated with both improved DFS (P ¼ 0.003) and BCSS (P ¼ 0.001) in tamoxifen untreated highrisk patients, such a correlation was not seen in tamoxifen-treated cases, the interaction was statistically significant (P ¼ 0.001). Multivariate analysis showed SRC3-pS543 to be an independent prognostic factor.Conclusions: Phosphorylation of SRC3 at S543 affects its genomic interactions on a genome-wide level, where SRC3-pS543 is selectively recruited to promoters of ERa-responsive genes. SRC3-pS543 is a prognostic marker, and a predictive marker of response to endocrine therapy. Clin Cancer Res; 22(2); 479-91. Ó2015 AACR.

show abstract

“…Steroid receptor coactivator (SRC)-1 was first identified to interact with NR in a ligand-dependent manner to enhance their transcriptional function ). Soon after this, two other proteins, transcriptional intermediary factor-2/ SRC-2 and amplified in breast cancer-1/SRC-3 (SRC-3) were cloned as NR coactivators that comprise the SRC coactivator family Gojis et al, 2010). Besides, the SRC family functions as coactivators not only for NR but also for multiple other transcriptional factors (TF), such as nuclear factor kappa B, E2F1 and IGF-1-dependent TFs (York et al, 2010;Ma et al, 2011;Walsh et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Steroid Receptor Coactivator-3 Promotes Bladder Cancer Through Upregulation of CXCR4

Wang¹,

Liu²,

Qu³

2013

Asian Pacific Journal of Cancer Prevention

View full text Add to dashboard Cite

The three homologous members of the p160 SRC family (SRC-1, SRC-2 and SRC-3) mediate the transcriptional functions of nuclear receptors and other transcription factors, and are the most studied of all the transcriptional co-activators. Recent work has indicated that the SRC-3 gene is subject to amplification and overexpression in various human cancers. Some of the molecular mechanisms responsible for SRC overexpression, along with the mechanisms by which SRC-3 promotes breast and prostate cancer cell proliferation and survival, have been identified. However, the function of SRC-3 in bladder cancer remains poorly understood. In the present study, our results indicate that overexpression of SRC-3 promotes bladder cancer cell proliferation whereas knockdown of SRC-3 results in inhibition. At the molecular level, we further established that CXCR4 is a transcriptional target of SRC-3. Therefore, our study first identified that SRC-3 plays a critical role in the bladder cancer, which may be a target beneficial for its prevention and treatment.

show abstract

The role of SRC-3 in human breast cancer

Abstract: nature reviews | clinical oncology volume 7 | marCH 2010 | 122 research highlights correction the role of Src-3 in human breast cancer Ondrej gojis, Bharath rudraraju, Mihir gudi, Katy hogben, sami sousha, charles r. coombes, susan cleator and carlo Palmieri

Cited by 51 publications

References 56 publications

The importance of Src signaling in sarcoma

The importance of Src signaling in sarcoma

SRC3 Phosphorylation at Serine 543 Is a Positive Independent Prognostic Factor in ER-Positive Breast Cancer

Steroid Receptor Coactivator-3 Promotes Bladder Cancer Through Upregulation of CXCR4

Contact Info

Product

Resources

About