A virus not known to cause disease kills triple-negative breast cancer cells and killed tumors grown from these cells in mice, according to Penn State College of Medicine researchers. Understanding how the virus kills cancer may lead to new treatments for breast cancer.
Adeno-associated virus type 2 (AAV2) infects humans but is not known to cause sickness. In prior studies, the researchers tested the virus on a variety of breast cancers that represent degrees of aggressiveness and on human papillomavirus-positive cervical cancer cells. The virus initiated apoptosis — natural cell death — in cancer cells without affecting healthy cells.
“Treatment of breast cancer remains difficult because there are multiple signaling pathways that promote tumor growth and develop resistance to treatment,” said Craig Meyers, Ph.D., Distinguished Professor of Microbiology and Immunology.
Signaling pathways involve molecules in a cell that control cell functions — such as cell division — by cooperation. For example, the first molecule in the process receives a signal to begin. It then tells another molecule to work, and so on.
Breast cancer is the most common cancer among women in the United States, the second most common cause of cancer death, and the main cause of death in women ages 45 to 55 years. In 2009, approximately 192,370 American women were diagnosed with breast cancer, and an estimated 40,170 women died of the disease.
Treatment of breast cancer differs by patient due to differences in tumors. Some tumors contain protein receptors that are activated by the hormones estrogen or progesterone. Others respond to another protein called human epidermal growth factor receptor 2, or HER2. Each of these is treated differently.
About 10-20% of breast cancers test negative for both hormone receptors and HER2 in the lab, which means they are triple-negative. Since hormones are not supporting its growth, the cancer is unlikely to respond to hormonal therapies, including tamoxifen; it is also is unlikely to respond to medications that target HER2, such as Herceptin or Tykerb.
Women with a BRCA1/2 mutation have a substantially higher risk of triple-negative breast cancer. African-American women are also at particularly high risk for the disease.
In addition, triple-negative breast cancer:
- Tends to be more aggressive than other types of breast cancer. Studies have shown that triple-negative breast cancer is more likely to spread beyond the breast and more likely to recur (come back) after treatment. These risks appear to be greatest in the first five years after treatment.
- Tends to be higher grade than other types of breast cancer. The higher the grade, the less the cancer cells resemble normal, healthy breast cells in their appearance and growth patterns. On a scale of 1 to 3, triple-negative breast cancer often is grade 3.
- Usually is a cell type called “basal-like.” “Basal-like” means that the cells resemble the basal cells that line the breast ducts. This is a new subtype of breast cancer that researchers have identified using gene analysis technology. Like other types of breast cancer, basal-like cancers can be linked to family history, or they can happen without any apparent family link. Basal-like cancers tend to be more aggressive, higher grade cancers — just like triple-negative breast cancers. It’s believed that most triple-negative breast cancers are of the basal-like cell type.
The aggressiveness of triple-negative breast cancer, combined with limited treatment options, makes it a more deadly disease.
“There is an urgent and ongoing need for the development of novel therapies which efficiently target triple-negative breast cancers,” Meyers said.
In the current study, the researchers tested AAV2 on a cell-line representative of triple-negative breast cancer. The researchers report their results in Cancer Biology & Therapy.
The AAV2 killed 100 percent of the cells in the laboratory by activating proteins called caspases, which are essential for the cell’s natural death. In addition, consistent with past studies, AAV2-infected cancer cells produced more Ki-67, an immunity system activating protein and c-Myc, a protein that helps both to increase cell growth and induce apoptosis. The cancer cell growth slowed by day 17 and all cells were dead by day 21. AAV2 mediated cell killing of multiple breast cancer cell lines representing both low and high grades of cancer and targeted the cancer cells independent of hormone or growth factor classification.
The researchers then injected AAV2 into human breast cancer cell line-derived tumors in mice without functioning immune systems. Mice that received AAV2 outlived the untreated mice and did not show signs of being sick, unlike the untreated mice. Tumor sizes decreased in the treated mice, areas of cell death were visible and all AAV2 treated mice survived through the study, a direct contrast to the untreated mice.
“These results are significant, since tumor necrosis — or death — in response to therapy is also used as the measure of an effective chemotherapeutic,” Meyers said.
Future studies will look at the use of AAV2 body-wide in mice, which would better model what happens in humans, according to Meyers.