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Normal and cancer-related functions of the p160 steroid receptor co-activator (SRC) family

Key Points

  • SRC1 was the first cloned steroid receptor co-activator that interacts with steroid hormone receptors to promote transcriptional activation in a hormone-dependent manner.

  • The p160 SRC family contains three homologous members, SRC1, SRC2 and SRC3, that interact with nuclear receptors and specific transcription factors. They recruit chromatin remodelling and other transcriptional enzymes to facilitate the assembly of general transcription factors for transcriptional activation.

  • SRCs are post-translationally modified in response to several upstream signalling pathways. These post-translational modifications determine or modulate SRC stability, subcellular localization, functional specificity, co-activator activity and/or co-activator complex assembly or disassembly.

  • SRC-knockout mice show that SRCs are involved in many physiological processes and each SRC has both specific and redundant physiological functions in embryonic and adult tissues.

  • SRC1 expression is increased in a subset of breast cancers and is positively correlated with ERBB2 positivity and poor disease-free survival rate. Knockdown of SRC1 in breast cancer cells inhibits cell proliferation.

  • Knockout of Src1 in mouse mammary tumour virus (MMTV)–polyoma middle T (PyMT) mice suppresses metastasis without affecting primary tumour formation. SRC1 promotes breast cancer metastasis by upregulating ERBB2, colony stimulating factor 1 and TWIST1 expression.

  • Both gene amplification and overexpression of SRC3 occur in a subset of breast cancers. SRC3 overexpression usually correlates with the expression of ERBB2, matrix metalloproteinase 2 (MMP2), MMP9 and polyoma enhancer activator 3, and with larger tumour size, higher tumour grade and/or poor disease-free survival.

  • SRC3 has an important role in promoting breast tumour cell proliferation, migration, invasion and metastasis through many mechanisms, such as increasing the function of oestrogen receptor-α and E2F1, the activity of the insulin-like growth factor 1 (IGF1) signalling pathway, epidermal growth factor receptor (EGFR) and ERBB2, and the expression of MMPs.

  • Knockout of Src3 in mice suppresses mammary tumour initiation, growth and metastasis, and overexpression of SRC3 in mouse mammary epithelial cells is sufficient to induce spontaneous mammary tumorigenesis.

  • SRC3 expression is increased during prostate tumorigenesis in mice. Knockout of Src3 efficiently arrests prostate tumour progression at a well-differentiated stage.

Abstract

The three homologous members of the p160 SRC family (SRC1, SRC2 and SRC3) 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 SRCgenes are subject to amplification and overexpression in various human cancers. Some of the molecular mechanisms responsible for SRC overexpression, along with the mechanisms by which SRCs promote breast and prostate cancer cell proliferation and survival, have been identified, as have the specific contributions of individual SRC family members to spontaneous breast and prostate carcinogenesis in genetically manipulated mouse models. These studies have identified new challenges for cancer research and therapy.

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Figure 1: Molecular structure of SRCs and their functional mechanisms in steroid hormone-induced gene expression.
Figure 2: Post-translational modifications of SRCs.
Figure 3: SRCs promote carcinogenesis through multiple pathways.

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Acknowledgements

This work was funded by US National Institutes of Health grants (R01DK058242, R01CA112403 and R01CA119689 to J.X.; P01DK059820, R01HD07857 and R01HD08818 to B.W.O.), National Institute of Diabetes and Digestive and Kidney Diseases-Nuclear Receptor Signalling Atlas, an American Cancer Society Research Scholar Award (ACS number RSG-05-082-01 to J.X.) and a Susan Komen for the Cure Award (BCTR0707225 to R.W.).

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pS2 gene

Agene that, in ERα-positive human breast cancer cells, such as MCF7 cells, is a direct target gene of ERα. On oestrogen treatment, pS2 mRNA expression can be substantially induced within 15 minutes.

Pituitary isograft

Implantation of a pituitary gland isolated from a syngeneic donor mouse into the kidney capsule of a recipient mouse. On stimulation of the implanted pituitary isograft, the recipient mouse shows significantly increased levels of prolactin, progesterone and oestradiol.

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Xu, J., Wu, RC. & O'Malley, B. Normal and cancer-related functions of the p160 steroid receptor co-activator (SRC) family. Nat Rev Cancer 9, 615–630 (2009). https://doi.org/10.1038/nrc2695

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