New Clues to Breast Cancer Development in High-Risk Women

Physicians who treat women with the breast cancer susceptibility gene BRCA1 often remove their patients’ ovaries to eliminate the source of estrogen they believe fuels cancer growth. Yet they also know that anti-estrogen therapies don't work to treat breast or ovarian cancer that might develop. That paradox has led scientists to question exactly how, or if, estrogen is involved in cancer development and whether removal of ovaries makes sense.

Now, a team of researchers from Georgetown University’s Lombardi Comprehensive Cancer Center have shed light on the mechanism that makes ovary removal protective against tumor development in this unique population.

They discovered that estrogen is needed to start the cancer process, but then the BRCA1 mutations somehow render the new tumors unresponsive to estrogen, producing cancer that is more aggressive and difficult to treat.

In a study published electronically on July 23 in the journal Oncogene, Georgetown researchers found that mutations of the BRCA1 gene can cause the estrogen-signaling pathway to go awry after cancer starts to grow. The mutated gene somehow causes the tumor cells to stop expressing the estrogen receptor, a protein that sits on the surface of the cell and recognizes the presence of the hormone. This means that these cancers lose sensitivity to estrogen (and potent anti-estrogen therapies like Tamoxifen) after tumors begin to form.

To show that estrogen was involved in the initiation of the cancer, the researchers overexpressed the estrogen receptor in a laboratory mouse model with a BRCA1 mutation and a p53 gene mutation (the two gene mutations usually coexist in human cancer). As predicted, they found that when exposed to estrogen, these mice developed cancerous tumors.

“Estrogen is definitely necessary for these tumors to develop, but somewhere along the tumor development pathway, the emerging tumors lose their sensitivity to estrogen,” said Priscilla Furth, MD, the study’s senior author and a professor of oncology at Georgetown. “The cells that develop into cancers frequently lose their ability to express the estrogen receptor and therefore are not sensitive to anti-estrogen therapies.”

Although the molecular mechanisms to explain this loss of sensitivity are not yet clear, the researchers believe that the BRCA1 mutation is causing the estrogen signaling pathway to malfunction, ultimately making these tumors harder to treat.

The findings also explain why the small proportion of women who have had an oophorectomy and still develop breast cancer frequently have tumors that are unresponsive to anti-estrogens like Tamoxifen, said Furth.

Both breast and ovarian cancers are often stimulated by estrogen, so oncologists counsel women who are over the age of 35 and know they carry a BRCA mutation to remove their ovaries—the body’s major source of estrogen—to reduce their chances of developing breast cancer and virtually eliminate risk of ovarian cancer, she explained.