A new research has pointed to a way to disrupt the tumor microenvironment of an aggressive form of breast cancer, which tends to be particularly aggressive, often resisting systemic chemotherapy and metastasizing to other tissues.
About 15 percent of breast cancers are classified as triple-negative, lacking receptors for estrogen, progesterone, and Her2. These cancers do not respond to targeted hormonal therapies.
Researchers had observed that triple-negative breast cancer (TNBC) patients who had higher numbers of a type of immune cell called myeloid-derived immunosuppressor cells (MDSCs) in their bloodstream had poorer outcomes. But until now it wasn’t clear how MDSCs are recruited to the primary breast tumor and how they contributed to its progression and spread.
A new report, led by researchers at the University of Pennsylvania, filled in crucial details about the connection between MDSCs and aggressive disease. Blocking the MDSCs themselves reduced tumor growth and metastasis in a mouse model of TNBC. The findings appeared in the Journal of Clinical Investigation.
“We’re excited because we think our findings could make a big difference for triple-negative breast cancer patients,” said researcher Rumela Chakrabarti. “Not only can deltaNp63 be used as a biomarker to help personalize treatment regimens, but targeting it may also provide an additive treatment for triple-negative breast cancer, in addition to chemotherapy and radiation.”
Earlier studies showed that increased levels of deltaNp63 were linked with breast cancer initiation. In the current work, the team of researchers found deltaNp3 was elevated in samples of TNBC patient’s primary tumors, as were numbers of MDSCs.
They used multiple mouse models and tissue transplants to see how manipulating the level of deltaNp63 affected the behavior of cancer, and they found lower levels corresponded with less metastasis to distant tissues. In addition, knocking down levels of deltaNp63 made the tumors much less aggressive, and it reduced numbers of MDSCs recruited to the tumor but not other immune cell types.
The researchers confirmed the relationship between deltaNp63 and MDSCs, showing that blocking two signaling molecules, CXCL2 and CCL22, activated by the protein reduced metastasis and blood-vessel growth associated with tumor growth, while increasing levels of these signaling molecules, caused MDSCs to boost the secretion of pro-tumor growth factors.
“How are the immune cells helping cancer cells?” Chakrabarti added. “It seems they are helping cancer stem cells grow faster.” Cancer stem cells can give rise to all the other cells in a tumor, just as normal stem cells can differentiate into other cell types. These cells are resistant to chemotherapy and radiation, which may explain why triple-negative breast cancer patients don’t respond to therapy.
The research team used small molecules to inhibit CXCL2 and CCL22 in human TNBC cell lines as well as in a mouse model of TNBC, a blockade that significantly reduced levels of MDSCs moving to the primary tumor and that substantially lowered signs of metastasis.
