Jefferson Researchers Discover Key Regulator of Hormonal Signaling in Breast Cancer Cells, Potential Drug Target
(PHILADELPHIA) Scientists at the Kimmel Cancer Center at Jefferson in Philadelphia have discovered new molecular evidence of the role of the hormone prolactin in breast cancer. They have found that prolactin, a pituitary hormone that normally stimulates breast development and milk production, initiates a new “signaling pathway” that may regulate the growth and survival of breast cancer cells.
The work, which appears this month in the journal Molecular Endocrinology, identifies the protein Jak1 as playing a key part in prolactin signaling in breast cancer. Jak1, which belongs to the cell growth-promoting tyrosine kinase class of enzymes, could represent a new drug target for treating breast cancer.
“In breast cancer cells, we found that Jak1 not only stimulates conventional prolactin signaling via proteins such as Stat5, but also that Jak1 recruited new signals, especially Stat3 and ERK,” says Hallgeir Rui, M.D., Ph.D., professor of Cancer Biology at Jefferson Medical College of Thomas Jefferson University and principal investigator of the study. “Because Stat3 and ERK typically are considered tumor-promoting, inhibitors of Jak1 may become useful in breast cancer treatment.”
Receptors for prolactin, have previously been shown to promote breast cancer cell growth, survival, and differentiation, Dr. Rui explains, through signaling pathways that involve activation of such proteins as Stat5, ERK, and Akt. Prolactin is also known to activate Stat3, which has been implicated as an oncogene involved in cancer cell growth and survival. In the current study, when Jak1 protein expression was experimentally disrupted in breast cancer cells, prolactin signaling through Stat3 and ERK was completely blocked. Signaling through Stat5 and Akt was reduced but still present.
“Until now, prolactin was believed to signal only through Jak2 to mediate its effects,” says Lynn Neilson, Ph.D., a postdoctoral fellow in the Department of Cancer Biology at Jefferson Medical College and first author of the study. “The unexpected finding that prolactin also activates Jak1 in breast cancer points to a mechanism in cancer cells that further promotes tumor cell growth.”
Dr. Rui’s laboratory currently is seeking to determine the role of Jak1 in breast cancer cell growth, survival, and invasion, which will be important for establishing the potential usefulness of Jak1 as a new drug target in patients. Prolactin is secreted by the pituitary gland, and important for milk production during lactation. Receptors for this hormone are present on a majority of breast cancers. Prolactin levels in blood are relatively unaffected by menopause, and breast cancer patients are exposed to the hormone across all age groups.
The study was funded by the National Institutes of Health and the Department of Defense.