Project description:Mufudza2012 - Estrogen effect on the dynamics
of breast cancer
This deterministic model shows the
dynamics of breast cancer with immune response. The effects of
estrogen are incorporated to study its effects as a risk factor for
This model is described in the article:
Assessing the effects of
estrogen on the dynamics of breast cancer.
Mufudza C, Sorofa W, Chiyaka
Comput Math Methods Med 2012; 2012:
Worldwide, breast cancer has become the second most common
cancer in women. The disease has currently been named the most
deadly cancer in women but little is known on what causes the
disease. We present the effects of estrogen as a risk factor on
the dynamics of breast cancer. We develop a deterministic
mathematical model showing general dynamics of breast cancer
with immune response. This is a four-population model that
includes tumor cells, host cells, immune cells, and estrogen.
The effects of estrogen are then incorporated in the model. The
results show that the presence of extra estrogen increases the
risk of developing breast cancer.
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Project description:Estrogen receptor positive breast cancer is the most prevalent form of breast cancer. Although a number of available drugs are highly effective at blocking estrogen mediated receptor activity, thousands of patients die every year from ER positive breast cancers because the disease progresses to a stage at which these drugs are no longer effective. Thus, it is crucial to establish a comprehensive understanding of the biology of the estrogen receptor (ER) in ER:positive breast cancers that progress despite hormone therapy, a gap in knowledge that remains a serious impediment to successful treatment of patients with ER positive breast cancer. A key question that must be answered is how the estrogen receptor retains the capacity to activate transcription in the absence or near absence of estrogen. We have found a partial answer to this question upon investigating the effect of amplification and overexpression of Wolf Hirschhorn Syndrome Candidate 1:Like 1 (WHSC1L1), a gene that is amplified in 15% of breast cancers that codes for a histone:lysine methyltransferase. WHSC1L1 lies in the 8p11:p12 amplicon, a region of gene amplification that is strongly associated with breast cancer. In this study, we performed shRNA knockdown of the catalytically inactive short isoform of WHSC1L1 in SUM44PE breast cancer cells and found that expression of the short isoform of WHSC1L1 is necessary for expression of the estrogen receptor in this highly ER:positive cell line. In addition, we found that the estrogen receptor binds chromatin extensively in the absence of exogenous estrogen, including several actively transcribed canonical ER target genes, indicating that estrogen receptor signaling is active in SUM44 cells in estrogen free conditions. These findings represent a novel model for ER biology in luminal B breast cancers harboring amplification of WHSC1L1 and provide insight into the mechanisms by which ER: positive breast cancers become unresponsive to SERMs or aromatase inhibitors.
Project description:Studying transcription factor (TF) interactions and gene regulatory networks in breast cancer, we have recently identified two distinct and opposing clusters of TFs associated with estrogen receptor-positive and -negative breast cancer and breast cancer risk. The relative activity of these two groups of TFs has a dramatic effect on patient outcomes and is likely to influence the phenotypic plasticity observed in breast cancer. We have identified two novel interactors (NFIB and YBX1) of the estrogen receptor (ESR1) using Rapid Immunoprecipitation Mass Spectrometry of Endogenous Proteins (RIME), co-immunoprecipitation and microscopy experiments. Both NFIB and YBX1 are members of the group of risk TFs that oppose the activity of the risk TFs associated with estrogen receptor-positive disease, and we have demonstrated that they both repress the transcriptional activity of ESR1. Here, we examine the effect of NFIB and YBX1 overexpression on the transcriptome of an estrogen receptor-positive breast cancer cell line to see if these risk TFs are able to repress the ESR1 regulon and drive cells towards a less estrogen-dependent phenotype. Overall design: Data consists of three different cell lines (MCF-7 parental, MCF-7 stably overexpressing FLAG-tagged NFIB, and MCF-7 stably overexpressing FLAG-tagged YBX1), analysed to detect gene expression differences. Each cell line was tested in triplicate (biological replicates consisting of three separate clones of stable cells).