New target for defeating breast cancer stem cells uncovered

Stashed away in most of your tissues and organs lie small populations of adult stem cells. They help keep our bodies functioning properly by replenishing dying or damaged cells. Their ability to make more copies of themselves, as needed, ensures that there’s always an adequate supply set aside. But this very same self-renewing, life-sustaining property of adult stem cells is deadly in the hands of cancer stem cells. Also called tumor-initiating cells, cancer stem cells sustain tumor growth even after chemotherapy and are thought to be a primary cause of cancer relapse.

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Microscopic image of normal mouse mammary ducts. Mammary stem cells are found among basal cells (green). Image courtesy of Toni Celià-Terrassa and Yibin Kang, Princeton University

By studying adult and cancer stem cells side-by-side, Princeton researchers report this week in Nature Cell Biology that they’ve uncovered a common function in both cells types that not only helps explain an adult stem cell’s self-renewing ability but also points to new therapeutic approaches to targeting breast cancer stem cells.

Both adult and cancer stem cells continually resist signals from their environment that encourage them to specialize, or differentiate, into a particular cell type. Once specialized, the cells lose their ability to self-renew and will eventually die off. Now, if all the adult stem cells in an organ followed that instruction, they would eventually become depleted and the organ would lose the ability to repair itself. The same holds true for cancer stem cells which actually would be a good thing since it would lead to the tumor’s death.

The Princeton team first identified a molecule called miR-199a that allows mammary (breast) stem cells to resist differentiation signals by directly blocking the production of a protein called LCOR. Artificially boosting the amount of miR-199a led to a decrease in LCOR levels and an increase in stem cell function. But when LCOR levels were increased, mammary stem cell function was restricted.

The researchers then turned their attention to breast cancer stem cells and found the same miR-199a/LCOR function at work. In a similar fashion, boosting miR-199a levels enhanced cancer stem cell function and increased tumor formation while increasing LCOR restricted the tumor-forming ability of the breast cancer stem cells.

These lab results also matched up with tissue samples taken from breast cancer patients. High miR-199a levels in the samples correlated with low patient survival rates. But those with high levels of LCOR showed a better prognosis.

It turns out that cells in our immune system are responsible for boosting LCOR in mammary and breast cancer stem cells by releasing a protein called interferon alpha. So the presence of interferon alpha nudges mammary stem cells to mature into mammary gland cells and inhibits breast cancer stems from forming tumors. But in the presence of elevated miR-199a levels, mammary and breast cancer stem cells are protected and maintain their numbers by deactivating the interferon alpha/LCOR signal.

If you’re still with me, these results point to miR-199a as a promising target for restoring interferon-alpha’s cancer interfering properties. Team leader Dr. Yibin Kang highlighted this possibility in a Princeton University press release:

“Interferons have been widely used for the treatment of multiple cancer types. These treatments might become more effective if the interferon-resistant cancer stem cells can be rendered sensitive by targeting the miR-199a-LCOR pathway.”

Breast Cancer Commandeers Mammary Stem Cells for Own, Nefarious Purposes

Most instances of breast cancer happen later in life—often after menopause. In many cases, the cancer progresses slowly, over a period of months or even years, often giving physicians precious time to implement a treatment plan, successfully battling that cancer into remission.

A section from a mammary 'outgrowth' harvested at lactation. [Credit: UC San Diego School of Medicine]

A section from a mammary ‘outgrowth’ harvested at lactation. [Credit: UC San Diego School of Medicine]

But there is another far more aggressive form of breast cancer that tends to develop earlier, often immediately following pregnancy. And now, researchers at the University of California, San Diego (UCSD) have discovered how this form of cancer hijacks a woman’s own stem cells to grow quickly and spread throughout the body.

Reporting in the latest issue of the journal Developmental Cell, UCSD stem cell researchers Drs. David Cheresh and Jay Desgrosellier and their teams have found a link between the molecular signaling switches that spur this aggressive, post-pregnancy breast cancer—and mammary stem cells that are normally activated during pregnancy.

These findings, say Cheresh, offer key insight into how scientists may develop better treatments for this form of breast cancer. As he stated in a news release:

“By understanding a fundamental mechanism of mammary gland development during pregnancy, we have gained a rare insight into how aggressive breast cancer might be treated.”

Normally, pregnancy activates a special group of stem cells in the mammary gland. Their job is to ready the expectant mother for feeding the newborn baby. By the time the baby is born, however, these stem cells go back into hibernation.

However, in some women, these mammary stem cells get hijacked by cancer cells. Rather than the mammary stem cells shutting down by the time milk production begins, cancer cells keep them switched on—which then contributes to the progression of cancer.

These findings shed much-needed light on the complex relationship between breast cancer and pregnancy. However, the authors caution that these findings don’t imply that becoming pregnant causes breast cancer. Rather, as Cheresh explained:

“Our work doesn’t speak to the actual cause of cancer. Rather, it explains what can happen once cancer has been initiated.”

Cheresh, who has received CIRM support for related work, has pinpointed a protein called CD61 that may promote the progression of breast cancer. CD61 has already been implicated in cancer metastasis and resistance to cancer drugs, so it makes sense that it would play a role in breast cancer as well.

Importantly, the discovery of a potential connection between CD61 and this form of breast cancer may ultimately open up new avenues for treating this type of cancer more successfully.

“Detecting CD61 might help doctors determine what kind of therapeutic approach to use, knowing that they might be dealing with a more aggressive yet treatable form of breast cancer. For example, there are existing drugs that block CD61 signaling, which might be another potential aspect of treatment.”

Want to learn more about breast cancer and stem cells? Check out our Solid Tumor Fact Sheet.