Breast Cancer Stem Cell Research
Breast cancer stem cells were discovered in 2003 by scientists at the U-M Comprehensive Cancer Center
In the fight against breast cancer, there is good news and bad news. The good news is that, since 1990, there has been a steady decline in the death rate from breast cancer. Earlier detection and better treatments are bringing hope to people with both early and advanced disease.
The bad news is that more than 40,000 people die from breast cancer every year in the United States alone. It is still the second-leading cause of deaths from cancer in women. The survival rate for those with advanced, metastatic breast cancer has not changed significantly for decades. In spite of more effective therapies, many patients still experience recurrences of breast cancer after treatment.
We believe that conventional therapies for advanced breast cancer are limited because they target the wrong cells. These therapies were designed to shrink cancers by killing all the cells in a tumor. We believe therapies could be more effective, and cause fewer side effects, if they were aimed specifically at a small group of cells within the tumor called cancer stem cells.
Breast cancer stem cells - the first to be identified in a solid tumor - were discovered in 2003 by scientists at the U-M Comprehensive Cancer Center. U-M scientists found that just a few cancer stem cells are responsible for the growth and spread of breast cancer. Unless the cancer stem cells are destroyed, the tumor is likely to come back and spread malignant cells to other parts of the body, a process called metastasis.
Because cancer stem cells are resistant to traditional chemotherapy and radiation, we need new treatments that can be targeted directly at these deadly cells. U-M Cancer Center scientists are studying breast cancer stem cells to learn more about them and to determine the type of therapy most likely to destroy the cells. The world's first clinical study of a treatment targeted at stem cells in breast cancer was conducted at the U-M Cancer Center and other clinical studies are currently in development.
How do scientists identify breast cancer stem cells?
All cells have a unique pattern of proteins, like a fingerprint, on their surface membranes. All breast cancer stem cells have a surface protein marker called CD44, along with very low levels or no levels of two markers called CD24 and lin. Using specialized equipment and techniques, scientists can separate cells with this combination of protein markers from millions of other cells in a tumor sample. U-M scientists also have identified a protein called ALDH, which is produced by cancer stem cells and can be detected in biopsies of patient tumors. Both genetic and non-genetic factors -- including age, radiation exposure, menstrual history and number of pregnancies -- are involved in the development of breast cancer.
What causes breast cancer?
Both genetic and non-genetic factors -- including age, radiation exposure, menstrual history and number of pregnancies -- are involved in the development of breast cancer.
For example, we know that women who inherit mutations in certain genes, especially BRCA1 and BRCA2, have a much higher risk of developing breast cancer. Mutations in HER2 and PTEN - genes involved in DNA repair and tumor suppression - are often present in aggressive breast cancers.
It is likely that some or all of these factors are involved in the development of breast cancer. But regardless of the triggering factor, U-M scientists believe that all types of breast cancer originate in stem cells, or cells called progenitors, which come from these stem cells in the breast.
What have U-M scientists learned about breast cancer stem cells?
Scientists at the U-M Cancer Center have been intensively studying breast cancer stem cells since their discovery in 2003. The more we know about these cells, the more likely we are to find ways to block their ability to drive the development of breast cancer. Every research advance provides an important clue that could lead to new treatments for the disease.
Recent discoveries by Cancer Center scientists include:
- Mutations in genes called HER2 and PTEN triggered rapid cell division and self-renewal in breast cancer stem cells. This caused the stem cells to develop abnormally and invade surrounding breast tissue. When the scientists treated the cells with drugs known to inhibit activity of these genes, the number of cancer stem cells dropped dramatically.
- In a study with mice, U-M scientists identified a receptor molecule on the surface of breast cancer stem cells and found that it triggered abnormal cell growth in response to tissue inflammation and damage caused by chemotherapy. When this receptor was blocked, the breast cancer stem cells died, preventing the cancer from spreading.
- U-M scientists discovered that progenitor cells in bone marrow called mesenchymal stem cells are involved in the development of breast cancer. The researchers found that breast tumors in mice sent out signals that caused mesenchymal stem cells to move from bone to the tumor. Once in the tumor, they stimulated cancer stem cells to divide and spread.
- A dietary component called sulforaphane, found in broccoli, killed breast cancer stem cells and prevented new tumors from growing in laboratory mice. Its ability to target cancer stem cells could explain sulforaphane's effectiveness in breast cancer prevention.
- U-M scientists found that curcumin, a component derived from the Indian spice turmeric, and piperine, derived from black peppers, decreased the number of stem cells in breast cells grown in a laboratory dish. The components had no effect on normal differentiated cells.
Do breast cancer stem cells cause metastasis?
There are many factors that trigger metastasis in cancer and scientists don't yet understand how they all work. But we do know that stem cells are involved in the process. Recent research by U-M Cancer Center scientists found that cells from tumors with a higher percentage of cancer stem cells were more likely to break away and spread.
Why are women still dying of breast cancer?
Advances in mammography and magnetic resonance imaging (MRI) screening for breast cancer have made it possible for doctors to see breast tumors when they are very small. When physicians can diagnose and treat breast cancer early, they often can remove the tumor with surgery and prevent a recurrence. Once malignant cells leave the primary breast tumor and migrate to other parts of the body, however, treatment is more difficult. Chemotherapy and radiation will kill most malignant cells and shrink the tumor, but the cancer often comes back, because these therapies don't kill the stem cells.
In addition, cancer stem cells drive metastasis - the tendency of malignant cells to spread throughout the body and form new tumors. Metastatic cancer is often what causes the death of women with advanced breast cancer.
To cure metastatic breast cancer, U-M scientists believe you must eliminate the cancer stem cells. Chemotherapy and radiation alone cannot do that.
Some breast tumors have more stem cells than others. Is that significant?
Research has shown that breast tumors with a higher percentage of cancer stem cells are more aggressive and more likely to spread. Women with these tumors have a higher risk of dying from cancer. So knowing the percentage of stem cells in a breast tumor could help determine which patients need more aggressive treatment.
Is there a link between BRCA1 mutations and cancer stem cells?
BRCA1 is a tumor suppressor gene known to be strongly linked to breast cancer. Mutations in this gene increase the risk of developing aggressive breast and ovarian cancer. Mutant forms of BRCA1 account for about 5% to 10% of cases of hereditary breast cancer. U-M Cancer Center scientists have discovered that BRCA1 regulates self-renewal of cancer stem cells. When the gene is mutated, cancer stem cells multiply abnormally, increasing the risk of cancer.
Are new treatments targeted at cancer stem cells being tested in U-M clinical trials?
In 2006, Cancer Center investigators began the world's first clinical trial of a treatment targeted at breast cancer stem cells. The study was designed to test the safety and tolerability of a new drug in 35 women with advanced, metastatic breast cancer that did not respond to traditional therapy. The experimental drug called MK-0752 blocks a signaling pathway involved in stem cell growth and development. Patients received the experimental drug in combination with chemotherapy. Researchers believe using a two-drug combination - one to kill cancer stem cells and one to kill the other cells in the tumor - will prove to be the best strategy.
Initial results from the trial were presented in December 2010 at the San Antonio Breast Cancer Symposium. Most patients enrolled in the study tolerated the side effects of the treatment. An examination of biopsies showed that the number of cancer stem cells in the tumor decreased after treatment. The pharmaceutical company that owns the experimental drug is determining whether to proceed with additional clinical trials.
Cancer Center researchers are planning more clinical trials of stem cell-based therapies for breast cancer.
How can I learn about clinical trials?
Information about is available on the Find a Clinical Trial web page. You can also call the Cancer AnswerLine™ at 800-865-1125.