Gene knock-out mouse model gives molecular clues to breast cancer

University of Cincinnati researchers say that new insights into the role of oestrogen receptor in mammary gland development may help understand the molecular origin of breast cancer.

Washington, September 6 : University of Cincinnati researchers say that new insights into the role of oestrogen receptor in mammary gland development may help understand the molecular origin of breast cancer.

US scientists at the National Institutes of Health (NIH) had developed a standard oestrogen receptor (ER) gene knock out mouse model a decade ago, in order to study the oestrogen receptor's role in human diseases. "Unfortunately, because these mice lacked mammary glands as a consequence of genetic manipulation, using this model to study the relationship between the oestrogen receptor and breast cancer proved ineffective," says Dr. Sohaib Khan, professor of cell and cancer biology at the university.

"Knocking out the oestrogen receptor gene for the entire genome, as the NIH scientists did, doesn't just affect the function of the receptor in all oestrogen-responsive organs. It also creates an imbalance in the body's circulating sex hormone levels, which could affect other physiological functions. An alternative model was clearly needed to study the intricacies of oestrogen receptors involvement in this disease," Khan adds.

Oestrogen receptor is a cellular protein that binds with the hormone oestrogen, and facilitates action in different parts of the body, including the mammary gland. Several studies have shown that in about 70 per cent case of breast cancer, tumours have some beneficial response to anti-oestrogen drugs like tamoxifen (marketed as Nolvodex).

After two years of work, Khan and his colleagues have developed a knock-out mouse model that will help scientists study the role of oestrogen receptor in specific organs, such as mammary glands, without affecting oestrogen-signalling throughout the rest of its body.

Khan says that he used a "conditional knock-out technique" to create the mouse model that retains oestrogen receptor in all tissues except mammary tissue, enabling his team to study the receptor's role in breast development and breast cancer.

Experiments with the mouse model showed that knocking out the gene only in mammary tissue resulted in abnormalities that compromised milk production in the nursing female. The finding suggests that oestrogen expression is essential for normal duct development during puberty, pregnancy, and lactation.

"Even though the relationship between the oestrogen receptor and breast cancer is well established, we still know very little about the receptor's mechanism of action. Unless we study those mechanisms more closely, improved strategies for breast cancer treatments will not be possible," says Khan, corresponding author of the study reported in the online edition of the Proceedings of the National Academy of Sciences.

Premenopausal women with breast cancer are currently given five years of tamoxifen, a drug that blocks the oestrogen receptor action in cancer cells, to prevent recurrence. Khan says that though the drug reduces recurrence in 40 per cent of the women who take it, many women eventually develop resistance to the drug.

Using this unique mouse model, the researchers are currently collaborating with scientists at Dana Farber Cancer Institute/Harvard Medical School to understand the relationship between oestrogen-signalling and oncogene-mediated breast cancer development.

They hope that their future research will furnish vital information about the molecular origin of breast cancer, and help scientists develop new drugs to more effectively treat the disease.

ANI