MYC and CSN5 in the Breast Cancer "Wound Signature" Profile

Institution: Stanford University
Investigator(s): Adam Adler, BA -
Award Cycle: 2006 (Cycle 12) Grant #: 12GB-0008 Award: $76,000
Award Type: Dissertation Award
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease



Initial Award Abstract (2006)
Cancer has been described as a wound that does not heal, since the molecular programs of normal wound healing are thought to be reactivated in cancer metastasis. Based on this concept, my mentorís laboratory (Dr. Howard Chang, Stanford University) previously identified a gene expression signature of 512 genes, termed the wound response signature that is a robust predictor of death and metastasis in breast cancer. While prognostic information from the wound signature is extremely useful, preventing and treating cancer is the ultimate goal. Understanding the biological basis of the wound signature would lead to a better understanding of the cancer itself and potentially lead to the identification of novel therapeutic targets to prevent breast cancer growth and metastasis. We discovered that amplifications of the chromosomal loci encoding MYC and CSN5 are sufficient to activate the wound signature and showed that these two genes functionally cooperate to induce changes that are associated with invasive tumor cells.

The aim of this project is to define the roles of MYC and CSN5 in a genetically defined human breast cancer cell line and to determine the requirement of CSN5 for breast cancer development in vivo using a genetically defined mouse model of breast cancer. MYC is a well known oncogene that was first identified as the cellular homolog of an avian viral gene. MYC is a transcription factor that has hundreds of targets, and it is known to be amplified in many types of cancer. MYC protein stability and activity is regulated by SCF ubiquitin ligase complexes, and CSN5 is believed to be a general activator of these SCF complexes.

Our experiments use mammary epithelial cells transformed through the addition of specific genetic elements also spontaneously induced clonal amplifications of MYC and CSN5. This system will enable dissection of the functional role of MYC and CSN5 to induce tumor growth. Further, using regenerated breast glands from transgenic mammary progenitor cells that produce breast tumors that resemble the human disease, we will further elucidate the requirement of MYC and CSN5 in tumor initiation and progression.

Studying the role of MYC and CSN5 in breast cancer progression will help lead towards an understanding of the mechanism underlying poor-prognosis, metastatic breast cancers. Tumors that express the wound signature have a two-fold increased risk of metastasis and a three-fold increased risk of death; however there are very few therapy options for these patients. The study proposed here has the potential to identify new therapeutic targets that could specifically inhibit the growth of these highly aggressive tumors, giving these breast cancer patients a new option for treatment.


Final Report (2008)
Cancer has been proposed to be "wounds that do not heal". This observation came about because normal wound healing and cancer growth share many features, such as rapid cell proliferation, cell migration, and new blood vessel growth. Previous work in our lab has lead to the observation that activation of two genes, CSN5 and MYC, can induce a set of genes involved in wound healing, which we call the "wound signature". The wound signature can robustly predict the risk of human breast cancer progression. While the role of MYC in many types of cancer has been extensively studied, the role of CSN5, a multi-functional signaling protein, in cancer development remained poorly understood.

The proposed project has been completed with great success. Using both human and mouse models of breast cancer, we have found a clear role for CSN5 and MYC in promoting breast cancer progression. The human breast cancer model was developed by introducing cancer-promoting genes into human mammary cells, and we observed that these cells lead to spontaneous activation of CSN5 and MYC. By inhibiting expression of CSN5 or MYC in this breast caner model, we found that both CSN5 and MYC are required for the tumorigenic properties of these cancer cells. We further observed that inhibiting both proteins simultaneously significantly reduced the expression of the wound signature profile and had an even stronger effect on reducing the growth potential of the cancer cells. Of note, the tumorigenic effects of CSN5 required components of its signaling complex and also the enzymatic activity of CSN5.

We then used a mouse model of breast cancer to show that CSN5 is also required for MYC-induced breast cancer growth in vivo. The mouse model we used involves removing normal mammary progenitor/stem cells from adult mice, introducing genes of interest into these cells, and then transplanting these cells into the mammary glands of young mice. These cells are able to form into normal mammary glands, however in the presence of tumor-promoting genes, the animals get breast cancer. Upon introducing MYC and another tumor-causing gene, RAS, the animals rapidly grow a very aggressive tumor that is similar to human breast cancers that express the wound signature. However, if we inhibit the activity of CSN5 by introducing a version of CSN5 that lacks its enzymatic activity, we significantly inhibit the growth of the breast tumors. In particular, we found that inhibiting CSN5 reduced the overall size of the tumors, and importantly it also reduced the tumor grade. These results confirm that MYC and CSN5 play a critical role in regulating breast cancer progression, and they pinpoint CSN5 enzymatic activity as a promising new therapeutic target in breast cancer progression.

Results of this research were published in two articles in Cancer Research (68:369-378 and 506-515, 2008) and in PLoS Genetics (3:91e, 2007).


Symposium Abstract (2007)
Normal wound healing and cancer growth share many features, such as rapid cell proliferation, cell migration, and new blood vessel growth. Thus, it has been proposed that cancers are "wounds that do not heal". Activation of two genes, CSN5 and MYC, can induce a set of genes involved in wound healing and predict the risk of human breast cancer progression. While the role of MYC in many types of cancer has been extensively studied, the role of CSN5, a multi-functional signaling protein, in cancer development remains poorly understood. Here we show that CSN5 is required for the tumorigenic properties of primary human breast cancer cells. The tumorigenic effects of CSN5 required components of its signaling complex, and the enzymatic activity of CSN5 was also essential. Inhibition of the enzymatic activity of CSN5 in a mouse model of breast cancer blocked breast cancer progression. These results pinpoint CSN5 enzymatic activity as a promising therapeutic target in breast cancer progression.

CSN5 isopeptidase activity links COP9 signalosome activation to breast cancer progression.
Periodical:Cancer Research
Index Medicus: Cancer Res
Authors: Adler AS, Littlepage LE, Lin M, Kawahara TL, Wong DJ, Werb Z, Chang HY
Yr: 2008 Vol: 68 Nbr: 2 Abs: Pg:506-15

CSN5 isopeptidase activity links COP9 signalosome activation to breast cancer progression.
Periodical:Cancer Research
Index Medicus: Cancer Res
Authors: Adler AS, Littlepage LE, Lin M, Kawahara TL, Wong DJ, Werb Z, Chang HY
Yr: 2008 Vol: 68 Nbr: 2 Abs: Pg:506-15

Revealing targeted therapy for human cancer by gene module maps.
Periodical:Cancer Research
Index Medicus: Cancer Res
Authors: Wong DJ, Nuyten DS, Regev A, Lin M, Adler AS, Segal E, van de Vijver MJ, Chang HY
Yr: 2008 Vol: 68 Nbr: 2 Abs: Pg:369-78

A transcriptional program mediating entry into cellular quiescence.
Periodical:PLoS Genetics
Index Medicus: PLoS Genet
Authors: Liu H, Adler AS, Segal E, Chang HY
Yr: 2007 Vol: 3 Nbr: 6 Abs: Pg:e91