Scientists have solved a key piece in the puzzle of how BRCA1 gene mutations specifically predispose women to breast and ovarian cancers. The answer is found in how estrogen rushes in to “rescue” cells whose healthy functioning has been altered by oxidative stress, a well-established factor in cancer development. Without estrogen, these damaged cells would die a natural death and not threaten the host in the long run. With estrogen, these cells survive, and also thrive and develop breast and ovarian cancers.
The research, published in the Journal of Experimental Medicine (2013; doi: 10.1084/jem.20121337), illuminates the interplay between the tumor suppressor gene BRCA1 and a master regulator, Nrf2, that governs the antioxidant response in cells. In healthy cells of all tissues, BRCA1, in partnership with Nrf2, normally repairs damaged DNA and protects cells against oxidative stress. However, when the BRCA1 gene is mutated, it loses its ability to repair DNA and can no longer partner with Nrf2, shutting off its antioxidative function. In most tissues, the resulting oxidative stress kills the cells that have lost BRCA1 function.
However, in the breast and ovary, the estrogen present in these tissues can swoop in to rescue BRCA1-deficient cells by triggering a partial turn-on of Nrf2. These unhealthy cells gain just enough resistance to oxidative stress to keep them alive and growing. Over time, these surviving BRCA1-deficient cells accumulate more and more mutations due to their lack of ability to repair DNA damage, eventually leading to the development of cancer in these tissues.
Co-author Tak Mak, MD, PhD, of Princess Margaret Cancer Center in Toronto, Canada, likens the actions of Nrf2 to a ceiling sprinkler that puts out visible flames (oxidative stress) but doesn’t reach the smoldering fire (cell damage) below.
He explained that their research confirms that anti-estrogens can delay the onset of breast and ovarian cancers in carriers of BRCA1 mutations. He said that the challenge is to find a way to block the antioxidant activity of estrogen without affecting its other activities that are necessary for female health. Modification of this one aspect of estrogen function would disrupt this significant cancer-initiating process while maintaining the positive effects of this hormone.
Genetically engineered mice were used to study the critical interaction between BRCA1, Nrf2, and estrogen in initiating women’s cancers. By examining the links between BRCA1 and oxidative stress in these mutant animals as well as in normal breast cells and breast tumors, the researchers were able to generate results that finally explain why loss of a tumor suppressor gene normally active in all tissues leads only to breast and ovarian cancers. The missing piece of the puzzle was estrogen and its unexpected effects on the antioxidant regulation mediated by Nrf2.