New research from the University of Michigan Comprehensive Cancer Center and Georgia Regents University finds that a protein that fuels an inflammatory pathway does not turn off in breast cancer, resulting in an increase in cancer stem cells. This provides a potential target for treating triple negative breast cancer, the most aggressive form of the disease. This is the conclusion of a study published in the February 17, 2014 edition of Nature’s journal Oncogene.
According to the American Cancer Society, breast cancer statistics: 235,030 Americans will be diagnosed with breast cancer this year and 40,430 will die from the disease. One of the most hard to treat breast cancers is triple-negative breast cancer or TNBC, which is defined as the absence of staining for estrogen receptor, progesterone receptor, and HER2/neu. One of the reasons why this cancer is hard to treat is that it is insensitive to some of the most effective therapies available for breast cancer treatment including HER2-directed therapy such as trastuzumab (Herceptin?; Genentech/Roche) and endocrine therapies such as tamoxifen (Nolvadex?; AstraZeneca) or the aromatase inhibitors. Combination cytotoxic chemotherapy administered in a dose-dense or metronomic schedule remains the standard therapy for early-stage triple-negative breast cancer.
…there are important links between inflammation and cancer, including similar pathways that regulate normal and cancer stem cells…
A protein called SOCS3
Now, researchers have identified a protein, SOCS3, that is highly expressed in normal cells but undetectable in triple-negative breast cancer. They showed that this protein is degraded in cancers, blocking the cellular off-switch of a feedback loop involving the inflammatory protein interleukin 6 or IL-6, which acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. When the switch does not get turned off, Il-6 enables and regulates cell growth and differentiation.
Inflammation and cancer
“We have known for a long time known that there are important links between inflammation and cancer, including similar pathways that regulate normal and cancer stem cells,” says study author Max S. Wicha, M.D., distinguished professor of oncology and director of the University of Michigan Comprehensive Cancer Center.
“This work helps explain why these pathways shut off in normal tissues after injury but remain active in cancers, resulting in an increase in cancer stem cells. Furthermore, they suggest that blocking these inflammatory loops may be a means of targeting cancer stem cells, improving patient outcome,” he noted.
Today,there are no molecularly targeted therapies aimed at triple-negative breast cancer, which is a type of cancer negative for estrogen receptor, progesterone receptor and the HER2-protein ? all key targets for current therapies. Patients with this form of disease tend to have worse outcomes.
Protein degradation
The researchers tested a drug, bortezomib, in mouse models of triple-negative breast cancer and found that it stops the protein degradation, resulting in the inflammatory loop shutting off, which reduces the cancer stem cells, thereby blocking metastasis. Bortezomib is currently approved for treatment of the blood cancer multiple myeloma.
This team previously showed that IL-6 can stimulate breast cancer stem cells in HER2-positive breast cancers and they are designing a clinical trial which uses an IL-6 blocker. The new research suggests that adding bortezomib to the IL-6 inhibitor may be a way to target stem cells in triple-negative breast cancer.
“Now that we unveiled how inflammation is regulated in triple-negative breast cancer, we expect that our studies can be translated into the clinic. The drugs used to block these chemical messengers are already approved for the treatment of rheumatoid arthritis and other inflammation-related diseases, which should facilitate their use in cancer,” says study author Hasan Korkaya, Ph.D., assistant professor at the Georgia Regents University Cancer Center.
More laboratory testing is needed before a clinical trial can begin. The researchers also suspect that this pathway may apply to other cancers as well and are investigating that further.
For more information:
Kim G, Ouzounova M, Quraishi AA, Davis A, Tawakkol N, Clouthier SG, Malik F, et al. SOCS3-mediated regulation of inflammatory cytokines in PTEN and p53 inactivated triple negative breast cancer model. Oncogene. 2014 Feb 17. doi: 10.1038/onc.2014.4. [Article][PubMed]
Copyright ? 2014 InPress Media Group/Sunvalley Communication. All rights reserved. Republication or redistribution of InPress Media Group/Sunvalley Communication content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group/Sunvalley Communication.InPress Media Group/Sunvalley Communication shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Onco’Zine and Oncozine are registered trademarks and trademarks of Sunvalley Communication around the world.
