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Wnt/B-Catenin And Egfr Signaling In The Metastasis Of Antiestrogen Resistant Breast Cancer To Bone
Investigator Initiated Research
Breast cancer affects nearly 1 out of 9 women in the US and a common devastating consequence is the severe pain and disability produced by bone metastasis. Breast cancer bone mestastases can be both osteoblastic (building inappropriate malformed bone) and osteolytic (bone matrix destroying) with the latter being more common. Estrogen receptor-positive tumors more frequently metastasize to bone than estrogen receptor-negative tumors. The development of selective estrogen receptor modulators (SERMs) such as tamoxifen has provided a relatively safe and effective treatment for early and advanced breast cancers that express this receptor. Unfortunately, the breast cancer cells in these patients will ultimately become resistant to tamoxifen or other SERMs and subsequently the disease will progress. We have recently developed tamoxifen and fulvestrant resistant cells from the estrogen receptor positive cell line MCF7 and characterized these using cDNA and promoter methylation arrays. Both resistant lines have increased ERBB2 signaling, whereas the fulvestrant resistant line also has elevated levels of EGFR and WNT signaling. In addition the fulvestrant resistant line has increased expression of a series of gene products previously identified to stimulate aggressive osteolytic growth of breast cancer cells. Therefore we tested the fulvestrant resistant cells in an animal models of breast cancer metastasis to bone. We found that the MCF7-F cells formed osteoltytic lesions whereas the parental MCF7 cells did not. We believe that WNT activated EGFR signaling synergizes with TGF? signaling to activate a bone metastasis program in the antiestrogen resistant cells. We will test this hypothesis with the following specific aims
Specific Aim 1: Investigate the impact of WNT and EGFR signaling on TGF?-induced expression of gene products associated with osteolytic growth of breast cancer cells. This in vitro study will first establish whether inhibition of WNT signaling alters EGFR activation and ligand expression. Inhibitors of both WNT and the EGFR pathways will be used to determine whether TGF?-induced activation of genes associated with osteoltyic growth in breast cancer cells can be blocked.
Specific Aim 2: Examine the effects of combinations of WNT/?-catenin and EGFR inhibitors on growth of breast cancer cells in the bone in vivo. In the first part of this aim, we will refine the MCF7-F model by selecting a derivative cell line that grows more rapidly in the bone after intracardiac injection. We will then use the intracardiac injection model of bone metastasis to investigate the effect of inhibitors of the WNT/?-catenin and EGFR on MCF7-F and MDA-MB-231 growth in this bone microenvironment.
These findings will point the way to treatments for patients with antiestrogen resistant tumors that have metastasized to bone.
In most cases cancer kills people by metastasis (traveling to distant sites) to vital organs and subsequent destruction of the tissue. This is the case for breast cancer patients as well. Metastasis is not entirely random process. In turns out that specific types of cancers frequently metastasize to certain locations. In the case of breast cancer, the vital organs that are most frequently associated with metastases tend to be bone, lung, brain and liver. Actually the bone is the most common site of breast cancer metastasis, and virtually all patients who succumb to the disease will have metastasis to this site. The growth of cancer cells in the bone leads to bone loss, fractures and severe pain. Growth of breast cancer cells in any organ is very dangerous to the patient, but traditional therapies such as chemotherapy have been somewhat effective in shrinking tumors in the lung, liver and brain. Traditional therapies have not been very successful in slowing the growth of breast cancer cells growing in the bone.
It has been known for some time that certain types of breast cancer cells are more likely to metastasize to bone. Breast cancers that have the receptor, which permits them to respond to the main female hormone estrogen are more likely to metastasize to bone. Fortunately, a set of drugs called antiestrogens, such as tamoxifen, have been developed that block the growth promoting effects of estrogen on breast cancer cells. These drugs typically are effective at blocking the growth of breast cancer cells for several years. Nevertheless, breast cancer cells eventually become resistant to these drugs and they begin to metastasize to other organs in the body, including the bone.
We have recently developed a model of this resistance by gradually growing cells in the lab in the presence of increasing concentrations of tamoxifen and another related drug, fulvesterant. Using a method that permitted us to simultaneously evaluate all of the genes used by these cells, we identified some pathways involved in breast cancer growth in bone were increased in the resistant cells. These resistant cells, in fact, were able to metastasize to bone in an animal model, but the parent cells could not. We believe that the activation of a single signaling program could underlie this change in behavior of these resistant cancer cells In this proposal, we want to test this hypothesis, and the determine whether blockade of this signaling system can inhibit the growth of the drug resistant cells in bone. We believe that these studies will lead to new treatments for patients with antiestrogen resistant breast cancer that has metastasized to bone. Also this information might help researcher to determine if certain antiestrogens will be more likely to contribute to bone metastasis than others in this class of drugs