August 17, 2011
Increased Estrogen Production Could Increase Risk of Breast Cancer
(Ivanhoe Newswire) "“ Some women who naturally produce excess estrogen in their breasts are at an increased risk for developing breast cancer, according to this study conducted by researchers at Georgetown Lombardi Comprehensive Cancer Center.
The investigators say their mice study shows that overproduction of aromatase, which converts testosterone into estrogen, in breast tissue is even more important in pushing breast cancer development than excess production of the estrogen receptor that the hormone uses to activate mammary cells. In addition, the researchers found that aromatase over-expressing mice also expressed more estrogen receptors on the breast cells.
While current breast cancer therapies target both of those processes "” inhibition of aromatase and inactivation of the estrogen receptor "” the researchers say this study suggests that aromatase inhibitors may prove to be a more potent choice for cancer prevention in postmenopausal women. Tamoxifen and other drugs that block the estrogen receptor have long been used to prevent breast cancer and deter recurrence, while aromatase inhibitors are only now being studied as a protectant.
"We know that estrogen is the fuel that most breast tumors use to grow, and this study shows us that making more estrogen in the breast, right next to cells that can use the hormone as fuel, appears to be a key trigger of early breast cancer," the study's senior investigator, Priscilla Furth, M.D., professor of oncology and medicine at Georgetown Lombardi, was quoted as saying.
"This study appears to help inform a longstanding controversy about whether it is systemic estrogen or estrogen produced in the breast that is the primary risk factor for breast cancer," Edgar DÃaz-Cruz, Ph.D., a postdoctoral researcher working in the Furth laboratory and first author of the study, was quoted as saying. "With our animal models, we've demonstrated that local production of estrogen in mammary tissue is potent enough to spur development of breast cancer, and does not require estrogen from the ovaries or produced from fat tissue, as had been hypothesized."
The researchers developed the first "conditional" mouse model of aromatase production in mammary tissue. That means they inserted a gene into mice that expresses human aromatase in the animal's mammary tissue "” a gene the researchers can turn on or off. They compared this new mouse model to one they had developed several years ago "”a conditional mouse model in which a gene that produces estrogen receptors (ER) could also be turned on and off.
While they study found that both mouse models experienced the earliest stages of tumor formation, known as preneoplasia, the aromatase over-expressing mice model exhibited both increased preneoplasia and outright development of cancer. These mice also expressed proteins that are tightly linked to cancer, Furth says.
The researchers also found, to their surprise, that aromatase over-expressing mice expressed more estrogen receptors than did the ER-conditional mice. "Increased aromatase produced both more estrogen and the receptors that the hormone needs to enter breast cells," said DÃaz-Cruz. "This is obviously a greater risk for development of breast cancer than just over-expression of estrogen receptors."
"In our conditional mice, aromatase provides a double whammy "“ more estrogen and more estrogen receptors," Furth noted.
Finally, they tested the effect of local versus systemic estrogen on development of preneoplasia. The researchers made three comparisons: between mice in which the ER was over-expressed; mice that had excess estrogen due to aromatase; and mice that were given more estrogen systemically. "If we give extra systemic estrogen, we don't see any increased risk of breast cancer, but the risk increases with extra expression of ER, and is higher still with local production of aromatase," said DÃaz-Cruz. "That suggests that estrogen production in the breast is an important risk factor for development of breast cancer."
What these results suggest for women is that if females vary in the amount of aromatase they naturally produce, as some studies suggest, then women with higher aromatase levels may be more susceptible to breast cancer, Furth said.
"Someday we may have a test available that can determine individual aromatase levels in postmenopausal women so that a preventive aromatase inhibitor can be prescribed to women at higher risk for breast cancer," Furth explained.
SOURCE: Cancer Research, published online August 16, 2011