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Elucidating the role of the transcriptional co-regulator CITED1 in hormone-dependent breast cancer

Mårtensson, Kira (2013) MOBM15 20122
Degree Projects in Molecular Biology
Abstract
CITED1 as a potential marker of treatment response in breast cancer

Background
Breast cancer is the most common form of cancer in women worldwide. In the clinic, breast cancer is generally divided into hormone dependent and independent form, based on whether tumor growth is driven by a certain hormone or not. Generally, patients with hormone-dependent breast cancer have a better prognosis compared to patients with hormoneindependent cancer, in part due to the availability of anti-endocrine therapies, e.g. Tamoxifen.

Estrogen is the sex hormone that is responsible for the majority of hormone-dependent breast cancers. Inside the cell, estrogen forms a complex with its receptor, estrogen receptor α (ERα), which translocates to the... (More)
CITED1 as a potential marker of treatment response in breast cancer

Background
Breast cancer is the most common form of cancer in women worldwide. In the clinic, breast cancer is generally divided into hormone dependent and independent form, based on whether tumor growth is driven by a certain hormone or not. Generally, patients with hormone-dependent breast cancer have a better prognosis compared to patients with hormoneindependent cancer, in part due to the availability of anti-endocrine therapies, e.g. Tamoxifen.

Estrogen is the sex hormone that is responsible for the majority of hormone-dependent breast cancers. Inside the cell, estrogen forms a complex with its receptor, estrogen receptor α (ERα), which translocates to the nucleus and binds to estrogen-responsive genes. Further, different proteins associate with this complex and modulate the transcription of the target gene (Figure 1). These associated proteins are known as coregulators and have an important function in regulating estrogen signaling. CITED1 has been identified as a co-regulator of estrogen, which enhances estrogen signaling. However, despite the growth-promoting effect of CITED1, its expression has been shown to correlate with better outcome. With this in mind, we wanted to further investigate the role of CITED1 in hormonedependent breast cancer, as well as to study the effects of CITED1 on tamoxifen treatment.

Results
We started the project with investigating a possible correlation between CITED1 and TAM treatment by using a publicly available database, GOBO. The obtained results showed that high CITED1 expression correlates with better outcome for patients with ERα-positive and tamoxifen treated tumors, compared to patients with low CITED1 expression.

The next step was to identify a model system that could be used in further experiments. We started by testing different breast cancer cell lines, luminal-like (ERα-positive) and basal-like (ERα-negative), for their expression of CITED1 using Western blot analysis. The results showed that in the tested cell lines, the expression of CITED1 protein was limited to the luminal, ERα positive cells. Among those, we chose T47D breast cancer cell line as a model system, due to the high expression of CITED1 and ERα. Furthermore, it is a well-established cell line in the cancer research. We further optimized the treatment conditions by testing different estrogen concentrations and time-points. When we treated the cells with estrogen, we saw a clear translocation of ERα to the nucleus and, even though not definite, a weak increase of CITED1 in the nucleus in response to the treatment. If so, this would confirm the hypothesized estrogen-CITED1 interaction. However, further investigation is required.

We also investigated the expression pattern of CITED2 and 4, other members of CITED-family. In comparison to CITED1, the expression of these two proteins is not limited to the luminal, ERα-positive breast cancer cell lines. This further emphasized the importance of CITED1 in ERα-positive breast cancer.

Advisor: Dr. Jill Howlin
Master Degree Project, 30 credits in Molecular Biology, 2013
Department of Biology, Lund University (Less)
Please use this url to cite or link to this publication:
author
Mårtensson, Kira
supervisor
organization
course
MOBM15 20122
year
type
H2 - Master's Degree (Two Years)
subject
language
English
id
3789330
date added to LUP
2013-05-21 12:40:17
date last changed
2013-05-21 12:40:17
@misc{3789330,
  abstract     = {CITED1 as a potential marker of treatment response in breast cancer

Background
Breast cancer is the most common form of cancer in women worldwide. In the clinic, breast cancer is generally divided into hormone dependent and independent form, based on whether tumor growth is driven by a certain hormone or not. Generally, patients with hormone-dependent breast cancer have a better prognosis compared to patients with hormoneindependent cancer, in part due to the availability of anti-endocrine therapies, e.g. Tamoxifen. 

Estrogen is the sex hormone that is responsible for the majority of hormone-dependent breast cancers. Inside the cell, estrogen forms a complex with its receptor, estrogen receptor α (ERα), which translocates to the nucleus and binds to estrogen-responsive genes. Further, different proteins associate with this complex and modulate the transcription of the target gene (Figure 1). These associated proteins are known as coregulators and have an important function in regulating estrogen signaling. CITED1 has been identified as a co-regulator of estrogen, which enhances estrogen signaling. However, despite the growth-promoting effect of CITED1, its expression has been shown to correlate with better outcome. With this in mind, we wanted to further investigate the role of CITED1 in hormonedependent breast cancer, as well as to study the effects of CITED1 on tamoxifen treatment.

Results
We started the project with investigating a possible correlation between CITED1 and TAM treatment by using a publicly available database, GOBO. The obtained results showed that high CITED1 expression correlates with better outcome for patients with ERα-positive and tamoxifen treated tumors, compared to patients with low CITED1 expression.

The next step was to identify a model system that could be used in further experiments. We started by testing different breast cancer cell lines, luminal-like (ERα-positive) and basal-like (ERα-negative), for their expression of CITED1 using Western blot analysis. The results showed that in the tested cell lines, the expression of CITED1 protein was limited to the luminal, ERα positive cells. Among those, we chose T47D breast cancer cell line as a model system, due to the high expression of CITED1 and ERα. Furthermore, it is a well-established cell line in the cancer research. We further optimized the treatment conditions by testing different estrogen concentrations and time-points. When we treated the cells with estrogen, we saw a clear translocation of ERα to the nucleus and, even though not definite, a weak increase of CITED1 in the nucleus in response to the treatment. If so, this would confirm the hypothesized estrogen-CITED1 interaction. However, further investigation is required.

We also investigated the expression pattern of CITED2 and 4, other members of CITED-family. In comparison to CITED1, the expression of these two proteins is not limited to the luminal, ERα-positive breast cancer cell lines. This further emphasized the importance of CITED1 in ERα-positive breast cancer.

Advisor: Dr. Jill Howlin
Master Degree Project, 30 credits in Molecular Biology, 2013
Department of Biology, Lund University},
  author       = {Mårtensson, Kira},
  language     = {eng},
  note         = {Student Paper},
  title        = {Elucidating the role of the transcriptional co-regulator CITED1 in hormone-dependent breast cancer},
  year         = {2013},
}