Regulation of SXR and Drug Resistance in Breast Cancer

Institution: Beckman Research Institute of the City of Hope
Investigator(s): Jennifer Murray, BA -
Award Cycle: 2002 (Cycle VIII) Grant #: 8GB-0081 Award: $41,984
Award Type: Dissertation Award
Research Priorities
Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure



Initial Award Abstract (2002)
Resistance to chemotherapy agents is a common problem in treating breast cancer. This drug resistance prevents many chemotherapy agents from being effective over an extended period of treatment. One possible component of multiple drug resistance is a protein known as SXR. SXR can interact with a wide variety of natural and synthetic hormones and chemotherapy agents. In response to these agents, SXR leads to increased levels of other proteins, such as Pgp, which pumps drugs out of the cell, and CYP3A4, which inactivates the drugs. The presence of these detoxifying proteins leads to reduced potency of drugs. Breast cancers have varying levels of SXR, and the role of SXR in breast cancer has yet to be determined. Because SXR activity leads to increased levels of drug detoxifying proteins, we believe that SXR is a key component of the multiple drug resistance phenomenon in breast cancer. Also, the action of SXR is controlled by certain proteins called coactivators and corepressors, but the exact details of this control - which coactivators and corepressors are most important - are not known.

We will determine if specific coactivators and corepressors are involved in promoting or preventing SXR activity in breast cancer. The presence or absence of these key proteins may eventually be used as important indicators for predicting the effectiveness of drug therapy.

We have made a breast cancer cell line that produces abundant SXR, but the SXR does not seem to be functional in these cells. We believe this is due to the absence of a critical coactivator(s) or the presence of a critical corepressor in our cells. We have begun looking at a variety of breast cancer cell lines for the presence or absence of specific coactivators and corepressors and will base our experiments on this data. Using standard cell culture methods, we will produce high amounts of a coactivator in our SXR-expressing breast cancer cells or reduce the levels of a corepressor in these cells. We hope this will restore SXR function, thereby showing that coactivators and corepressors are important in controlling SXR activity.

The role of SXR and its coactivators and corepressors in breast cancer has not been established. This proposal will determine which proteins are involved in controlling SXR activity. In the future, we may be able to monitor breast cancers for the presence of SXR and its regulatory proteins and thereby determine which breast cancers will be less responsive to certain chemotherapy agents. By targeting SXR and its regulatory proteins for therapeutic intervention, it may be possible to make chemotherapy drugs more effective.


Final Report (2004)
Drug resistance is an important problem in the treatment of breast cancer. Many chemotherapy agents become less effective over a course of treatment because the cancer cells have become resistant to the drugs. A protein known as SXR may be involved in drug resistance. Through its interactions with chemotherapy agents, SXR causes an increase in proteins that detoxify the cells, such as P-gp, which pumps drugs out of the cell, and CYP3A4, which inactivates the drugs. The increased levels of these proteins prevent chemotherapy drugs from being effective. SXR is expressed at varying levels in breast cancers. We believe that SXR is a key regulator of drug resistance in breast cancer cells since its activity results in an increase of detoxifying proteins. SXR activity is regulated by proteins known as coactivators or corepressors, but which of these factors are most important in regulating SXR has yet to be determined. We are investigating the regulation of SXR activity in breast cancer by specific coactivator and corepressor proteins.

We made a breast cancer cell line that produces high levels of SXR, but we have not seen evidence of SXR function in these cells. The activity of SXR was lower in our breast cancer cells than in control colon cancer cells. We looked for another protein called RXR that SXR binds to and needs in order to be active. We saw RXR protein in our breast cancer cells that produce SXR and in control cells, so we can rule out the lack of RXR as a reason that SXR is not active. We then began looking at the levels of coactivator and corepressor proteins present in different types of breast cancers and in other types of cancer cells, such as colon and liver. One coactivator, called DRIP205, was present only at low levels in our SXR-expressing breast cancer cells while control colon cancer cells produce more of this coactivator. We added this coactivator to our breast cancer cells to see if it resulted in greater SXR activity. However, even with the addition of DRIP205, we did not see an increase in SXR activity in these cells. Therefore, we concluded that DRIP205 does not have a major role in regulating SXR. Analysis of other coactivator proteins showed that our SXR-expressing breast cancer cells do express GRIP-1, ACTR, or SRC-1 at similar or higher levels as control cells. While our SXR-expressing breast cancer cells do have the corepressors SMRT and NCoR, they have less of these potentially inhibitory proteins than control cells. Therefore, we believe that SXR activity is regulated in a more complex way than by just the simple presence or absence of various coregulatory proteins.

There are many known nuclear receptor coregulatory proteins other than the ones we have analyzed, so we will continue trying to identify critical coactivator(s) and corepressor(s) responsible for regulating SXR activity. These coregulatory proteins also need to interact with SXR to modulate its activity, and we will try to determine which proteins bind to SXR in our breast cancer cells versus control cells. The presence of SXR and its cofactors in breast cancer may be important determinants of a patientís response to chemotherapy. We now have a better understanding of which coregulatory proteins are expressed in various types of breast cancers. By understanding how SXR is regulated, we may be able to prevent SXR-mediated drug resistance, thereby allowing chemotherapy agents to become more effective.


Symposium Abstract (2003)
Resistance to chemotherapy agents is a common problem in treating breast cancer. This drug resistance prevents many chemotherapy agents from being effective over an extended period of treatment. One possible component of multiple drug resistance is a protein known as SXR. SXR can interact with a wide variety of natural and synthetic hormones and chemotherapy agents. In response to these agents, SXR leads to increased levels of other proteins, such as Pgp, which pumps drugs out of the cell, and CYP3A4, which inactivates the drugs. The presence of these detoxifying proteins leads to reduced potency of drugs. Breast cancers have varying levels of SXR, and the role of SXR in breast cancer has yet to be determined. Because SXR activity leads to increased levels of drug detoxifying proteins, we believe that SXR is a key component of the multiple drug resistance phenomenons in breast cancer. Also, the action of SXR is controlled by certain proteins called coactivators and corepressors, but which coactivators and corepressors are most important is not known.

We have made a breast cancer cell line that produces abundant SXR, but the SXR does not seem to be functional in these cells. We believe this is due to the absence of a critical coactivator(s) or the presence of a critical corepressor in our cells. We have begun looking at a variety of breast cancer cell lines for the presence or absence of specific coactivators and corepressors. One coactivator in particular, a protein called DRIP205, is present only in low levels in our SXR-expressing breast cancer cells. However, this coactivator does not seem to be necessary for SXR activity. We have also seen different levels of SXR activity in different breast cancer cells and other cell types, suggesting that the cellular environment has a large influence on SXR activity.

We are hoping to determine the role of SXR and its coactivators and corepressors in breast cancer. In the future, we may be able to monitor breast cancers for the presence of SXR and its regulatory proteins and thereby determine which breast cancers will be less responsive to certain chemotherapy agents. By targeting SXR and its regulatory proteins for therapeutic intervention, it may be possible to make chemotherapy drugs more effective.