Activation of HERV-K env Protein is Essential for Oncogene-Induced Breast Tumorigenesis
Abstract
This research addresses two overarching challenges for breast cancer. The first challenge is to identify what drives breast cancer growth and determining how to stop it, and the second is eliminating the mortality associated with metastatic breast cancer. We have discovered a retrovirus present in all humans that becomes expressed in early breast cancer and continues to be expressed in breast cancer even after the cancer has metastasized. Therefore, it if we can block this virus, we may be able to prevent a gene that is driving breast cancer until it metastasizes. This retrovirus is called human endogenous retrovirus type K (HERV-K), and it became incorporated into the genes of primates and was passed on to humans. Our laboratory showed that HERV-K is expressed in early breast cancer, but our recent and somewhat surprising finding is that HERV-K is needed for breast cancer to spread to other organs. Since metastasis is responsible for the death of breast cancer patients, anything that can be done to prevent it would almost certainly be welcomed by breast cancer patients. Our first inkling that HERV-K may be important in breast cancer metastasis came from a study published this year, where we found that HERV-K may be able to predict metastasis in women who are diagnosed with breast cancer. HERV-K tended to be higher in breast cancer patients with a primary tumor who later on developed the metastatic disease than in patients who did not develop metastasis. The next step in our discovery of the harmful effect of HERV-K on breast cancer metastasis came when we inserted a knockout version of HERV-K into human breast cancer cells, and then allowed them to grow in mice (the mice were immunodeficient so that they would not reject the human cells). The knockout version used a special genetic tool to cause HERV-K expression to stop in the breast cancer cells. When we looked at the lungs and other organs of these mice, breast cancer cells with HERV-K knocked out did not appear in the cells -- the breast cancer did not metastasize. Our hypothesis is that HERV-K acts as a cancer protein (oncoprotein) and plays an essential role in promoting breast cancer tumorigenesis and metastasis. Thus, it is an excellent target for detection, chemotherapy, and immunotherapy. To test this hypothesis, we have four specific aims: Aim 1: Explore whether changes occur in the region controlling HERV-K expression in metastatic breast cancer patients. Aim 2: Find whether the site where HERV-K integrates into the genome of breast cancer patients is different from the site in women without breast cancer. Aim 3: Assess HERV-K expression and its mechanism of action in drug-resistant breast cancer cell lines. Aim 4: Determine whether overexpression of HERV-K will enhance breast cancer metastasis in animal models. Our research is ultimately applicable to metastatic breast cancer patients. It is estimated that about 40,000 women die from the disease each year due to metastasis, and our new target associated with metastasis may help a significant fraction of these women. Our research is aimed at preventing and treating both metastatic and non-metastatic breast cancer, and to do this we have one major objective of determining whether knocking down HERV-K will prevent breast tumor growth and metastasis. HERV-K is the same type of virus as HIV (human immunodeficiency virus), and drugs to treat HIV have turned AIDS (acquired immune deficiency syndrome) into a chronic disease. Since HERV-K drives metastasis by activating Ras and other oncogenes, we will also determine exactly how HERV-K acts to promote breast cancer and its metastasis, i.e., determine its mechanism of action in Aims 1and 2. We additionally want to find a drug that inhibits HERV-K, which should then block breast cancer metastasis. Finally, we have some strong evidence that HERV-K knockdown acts synergistically with breast cancer drugs to kill breast cancer cells, and we will det
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510530
Entities
People
- Feng Wang-johanning
Organizations
- SRI International
- United States Army