Dr. Christopher Mueller
Christopher R. Mueller
Office Phone: 613-533-6751
- Professor of Biochemistry and Pathology & Molecular Medicine
- BSc, Carlton University
- PhD, McGill University
Dr. Mueller's Lab
Stress and Breast Cancer
There has been considerable anecdotal information and epidemiological data suggesting that psychological stress can lead to an increase in breast cancer incidence. Current studies place the increased risk due to the loss of a close partner or family member at an odds ratio of 1.8 or higher. While this is comparable to other known risk factors, the potentially large population which is exposed to greater and greater stress is of concern. Up to now, a molecular mechanism which could explain a breast specific increase in cancer has been lacking. Through our investigations of the regulation of the BRCA1 gene expression we have found that the stress hormone cortisol is able to decrease the expression of this important tumour suppressor gene. Increased stress would lead to decreased BRCA1 levels, reducing the tumour suppressor activity in those affected breast cells and potentially leading to increased transformation. We continue to investigate the basis for this regulation, particularly focusing on molecular pathways, but also examining genetic and environmental effects which could modulate an individual woman’s susceptibility to stress.
BRCA1 and Sporadic Breast Cancer
We still do not understand the basic origin and development of breast cancer. It is clear that loss of functional BRCA1 and 2 genes lead to the frequent development of breast cancer in familial cases of the disease. However in sporadic breast cancer, which makes up 90% of the cases of breast cancer, these genes are not mutated. We have been pursuing the theory that sporadic breast cancer results from the decreased expression of the BRCA1 gene, leading to loss of its tumor suppressor function. There is a great deal of clinical evidence to suggest that loss of BRCA1 expression occurs in almost all sporadic tumors and that the magnitude of this loss is proportional to the level of malignancy of the tumor. We believe that loss of BRCA1 expression is the main precipitating event in breast transformation, and leads directly to tumor formation as is the case in familial tumors. Click on this link to see a recent review from the lab. We have been able to identify a number of different transcription factors which interact with the BRCA1 promoter and it appears that alterations in certain of these factors may be responsible for the decrease in BRCA1 seen in sporadic tumors.
Figure 1. Model of sporadic breast cancer transformation. Loss of BRCA1 or 2 can occur by mutation of the gene or loss of expression. Recently, the EMSY gene has been identified which is amplified in some tumors and which inactivates BRCA2 function.
Breast Cancer Risk and BRCA1 Levels
Figure 2. Some potential interactions which could link a variety of risk factors with BRCA1 levels.
This work led us to consider the possibility that the level of expression of BRCA1 may also play a role in determining the risk of a woman developing breast cancer. We have recently observed that the stress hormone hydrocortisone is able to suppress the expression of BRCA1. This may provide us with a biological link between stress and the development of breast cancer in the human population. We believe that BRCA1 levels in breast cells may determine the relative susceptibility of the breast to transformation. This may be both in terms of increasing or decreasing risk in an individual. It is possible that many other risk factors such as pregnancy, exposure to environmental carcinogens, diet and other hormonal changes such as age at puberty, may also act through this mechanism. By bringing a new unified theory of breast cancer risk to the field we believe that this work can significantly enhance our understanding of how these processes function. While epidemiological studies have been very successful in identifying risk factors for breast cancer, the lack of an understanding of the fundamental biological processes which underlie these effects has naturally limited the level of insight into these effects.
BRCA1 and Ovarian Cancer
BRCA1 is also a tumor suppressor gene involved in the development of ovarian cancer. The situation with sporadic ovarian cancer is very similar to that of sporadic breast cancer. No mutations in this gene are found in sporadic tumors, but the level of BRCA1 in these tumors is consistently decreased and is correlated with the level of malignancy of these tumors. Our laboratory has an ongoing collaboration with Dr. Calvin Roskelley at the University of British Columbia examining the regulation of the BRCA1 promoter in the context of ovarian transformation. See our recent review on this subject.
In Vitro Models of Breast Differentiation
We have been taking advantage of in vitro models of breast differentiation. This uses cell lines such as mouse EPH-4 cells which are plated on Martigel, which mimics the basement membrane. The cells form hollow balls, referred to as mammospheres, which resemble breast end buds. When the hormones prolactin, insulin and hydrocortisone are added these cells polarize and start to produce milk proteins. We are using them to ask questions about cell organization, differentiation and transformation.
Figure 3. EPH-4 on Matrigel and treated with hormones produce milk proteins.
We have also been studying the Sp1 family of transcription factors. Sp1 was one of the first transcription factors cloned and was thought to be a constitutive factor which was not regulated. We have demonstrated that it is phosphorylated during the terminal differentiation of a number of cell types. Another family member called Sp3 is expressed in parallel with Sp1 and binds to the same recognition elements. Sp3 was one of the first factors to be deomonstrated to be SUMOylated, which is a post-translational modification similar to ubiquitination, but which causes changes in its sub-nuclear localization. It also modifies its ability to act as an activator or repressor. We are examining the effect of these proteins on the regulation of the p21CIP1/WAF1 gene in the context of the regulation of growth arrest, and their effect on the Telomerase Reverse Transcriptase (TERT) gene in relation to immortalization.
- Thompson C, MacDonald G, Mueller CR. Decreased expression of BRCA1 in SK-BR-3 cells is the result of aberrant activation of the GABP Beta promoter by an NRF-1 containing complex. Molecular Cancer. 2011 May 24;10:62.
- Antonova L, Aronson K, Mueller CR. Stress and Breast Cancer: From Epidemiology to Molecular Biology. Breast Cancer Res. 2011 Apr 21;13(2):208.
- Antonova L, Mueller CR. Hydrocortisone down-regulates the tumor suppressor gene BRCA1 in mammary cells: a possible molecular link between stress and breast cancer. Genes Chromosomes Cancer 47:341-352, 2008.
- Sam MR, Elliott BE, Mueller CR. A novel activating role of SRC and STAT3 on HGF transcription in human breast cancer cells. Mol Cancer 6:69, 2007.
- MacDonald G, Stramwasser M, Mueller CR. Characterization of a negative transcriptional element in the BRCA1 promoter. Breast Cancer Res. 9:R49, 2007.
- Graves ML, Zhou L, MacDonald G, Mueller CR, Roskelley CD. Regulation of the BRCA1 promoter in ovarian surface epithelial cells and ovarian carcinoma cells. FEBS Lett. 581:1825-1833, 2007.
- Kraft CS, LeMoine CM, Lyons CN, Michaud D, Mueller CR, Moyes CD. Control of mitochondrial biogenesis during myogenesis. Am J Physiol Cell Physiol 290:C1119-C1127, 2006.
- Wojcik EJ, Sharifpoor S, Miller NA, Wright TG, Watering R, Tremblay EA, Swan K, Mueller CR, Elliott BE. A novel activating function of c-Src and Stat3 on HGF transcription in mammary carcinoma cells. Oncogene 25:2773-2784, 2006.
- Hammill D, Jain N, Armstrong S, Mueller CR. The D-domain of Sp3 modulates its protein levels and activation of the p21(CIP1/WAF1) promoter. Biochem Biophys Res Commun 335:377-384, 2005.
- McClelland GB, Kraft CS, Michaud D, Russell JC, Mueller CR, Moyes CD. Leptin and the control of respiratory gene expression in muscle. Biochim Biophys Acta. 1688:86-93, 2004.
- McCoy ML, Mueller CR, Roskelley CD. The role of the breast cancer susceptibility gene 1 (BRCA1) in sporadic epithelial ovarian cancer. Reprod Biol Endocrinol 1:72, 2003 (Review).
- Mueller CR, Roskelley CD. Regulation of BRCA1 expression and its relationship to sporadic breast cancer. Breast Cancer Res. 5:45-52, 2003 (Review).
- Atlas E, Stramwasser M, Mueller CR. A CREB site in the BRCA1 proximal promoter acts as a constitutive transcriptional element. Oncogene 20:7110-7114, 2001.
- Atlas E, Stramwasser M, Whiskin K, Mueller CR. GA-binding protein alpha/beta is a critical regulator of the BRCA1 promoter. Oncogene 19:1933-1940, 2000.
last updated: 20 January 2012