Acid Accumulation in Breast Cancer Disables Powerful Protective Hormone
(PHILADELPHIA) Runners often say their legs have gone sour because of the build-up of lactic acid in their muscles. Some breast tumors also produce lactic acid — and that makes them, mysteriously, aggressive and resistant to treatment. Now, a research team at Thomas Jefferson University's Kimmel Cancer Center has found out why that occurs.
In some breast tumors, the acid environment produced by lactic acid disables a key protective hormone signaling pathway, according to the study published September 3rd online in Breast Cancer Research.
This pathway, prolactin-Stat5, keeps breast cells growing in a differentiated state — that is, it maintains some of the features of normal cells, says the study's senior investigator, Hallgeir Rui, MD, PhD, Professor of Cancer Biology, Medical Oncology and Pathology and Scientific Director of Jefferson Breast Care Center.
"Without this pathway intact, breast cancer cells morph into a dangerous undifferentiated state," he says.
"It is known that lactic acid is an unwanted leftover after tumors — and the muscles in runners — break down glucose to generate energy. Now we understand that the acidosis that is produced in breast cancer allow tumors to evolve more aggressive features because it leads to loss of prolactin–Stat5 signaling," Dr. Rui says.
The finding is the culmination of a long look at prolactin-Stat5 by Dr. Rui and his team of collaborators.
Dr. Rui was the first scientist to isolate a prolactin receptor-associated tyrosine kinase, and his team linked disruption of this pathway to breast cancer progression and therapy resistance. For example, in estrogen-receptor-positive breast cancer, loss of Stat5 is associated with increased risk of anti-estrogen therapy failure.
This study reveals a biological mechanism behind loss of that pathway. "The prolactin hormone is no longer able to bind to its receptor even in a mildly acidic environment," says Ning Yang, PhD, first author of the article.
Dr. Rui says the findings may offer some possible therapeutic avenues. "Reversing acidosis or removing it may allow prolactin receptors to work normally, but this could be very difficult to achieve," he says. We are exploring some alternative ideas, Dr. Rui says. "It might also be possible to help select drugs for patients by testing whether their breast cancer has a marker that signals an acidic environment," he adds.
"Finding the reason why loss of this important pathway leads to aggressive breast cancer helps us fit in a big piece of the puzzle we have been working on for a long time," he says. "We are looking forward to translating these findings to benefit our breast cancer patients."
The authors declare that they have no conflicts of interest.
This work was supported by Komen for the Cure Promise grant KG091116, National Cancer Institute grant 1P30CA56036, and a Commonwealth University Research Enhancement Program grant with the Pennsylvania Department of Health.
For more information, contact Edyta Zielinska, (215) 955-5291, Edyta.Zielinska@jefferson.edu.