Dr. Lisanti explains that he and his colleagues had wanted to test the hypothesis that the loss of a functioning Caveolin-1 gene could increase the activity, or "upregulate" the expression of estrogen receptors. Only 5 to 10 percent of the cells in the normal human breast express estrogen receptors, yet the receptor activity for some reason rises dramatically in premalignant lesions and cancer.
Dr. Lisanti's team developed mice lacking the Caveolin-1 gene and found a dramatic increase in both number and activity of estrogen-positive receptors in mouse breast tissue, specifically in breast epithelial cells, in turn, promoting cell growth. Caveolin-1, Dr. Lisanti suggests, could act as a kind of "switch" that regulates receptor activity and cell proliferation.
"It is the first time that we can say that the loss of function of caveolin gene expression plays a role in the specific upregulation of estrogen receptor," he says. "It helps explain the nature of this transition from nonmalignant to malignant tissue."
Dr. Lisanti explains that estrogen receptors are thought to help turn on certain genes such as cyclin D1, which in turn promote cancer development. "We've elicited a new pathway for mammary tumorigenesis," he says. "Before, we could say that estrogen receptors turned on cyclin D1, which was enough to cause mammary tumorigenesis. Now we've added another link: inactivation of caveolin as the first initiation step."
The team found that cyclin D1 activity in human breast cancer samples was increased, specifically after estrogen treatment. "In essence, we have created a preclinical model in which to study the role of estrogen and caveolin deficiency in breast cancer development," he says. "It's a new signaling pathway for understanding the pathogenesis of human breast cancer with caveolin gene inactivation as the initiating step. It all fits togethe
Source:Thomas Jefferson University