Female hormones key to breast and ovarian cancer in BRCA mutation carriers

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Women with the faulty genes BRCA1 and BRCA2 have abnormal levels of female hormones in the bloodstream, which leads them to develop breast and ovarian cancer rather than other cancers, according to new research.

"We have shown for the first time that cancer risk in BRCA1 and BRCA2 [mutation] carriers is not just caused by local defects in the ability of cells to repair themselves. An additional systemic problem—abnormal levels of female hormones in the bloodstream and altered downstream effects—is the likely explanation as to why BRCA1/2 mutation carriers develop breast and ovarian cancer rather than other cancers,” said lead author Professor Martin Widschewendter, MD, MRCOG, head of the Women's Cancer Department at University College London in the United Kingdom.

According to the results of the study, published in Lancet Oncology (2013; doi:10.1016/S1470-2045(13)70448-0), women with BRCA1 or BRCA2 mutations are exposed to different levels of the female hormones oestradiol and progesterone. These are already known to be risk factors for breast and ovarian cancer. These differences could not be explained by contraceptive pill use.

This study indicates that BRCA mutation carriers have abnormal hormone regulation, possibly due to a mechanism linked to the altered BRCA genes in the carriers' ovaries. Another possibility is that BRCA gene alterations change the sensitivity of tissues to hormones.

The research team analyzed 1,966 measurements of the thickness of uterine linings from ultrasounds. They compared 1,573 measurements in women negative for both mutations with 203 measurements from carriers of altered BRCA1 and 190 with altered BRCA2. The thickness of the uterus lining, or endometrium, is known to depend at least partly on the levels of female hormones. So, the researchers also measured the concentrations of these hormones in the participants' bloodstreams.

The carriers of the BRCA1/2 mutations were found to have higher concentrations of female hormones. Also, the differences in the hormone levels correlated with the differences in the thickness of the endometrium in the second half of the menstrual cycle.

Based on these findings, research has already begun into how estrogens affect the Fallopian tubes, as this is where the majority of ovarian cancers in BRCA1/2 mutation carriers actually start. The goal is to design drugs that might prevent the carcinogenic effect of high concentrations of estrogens in the Fallopian tube.

The other female hormone, progesterone, is known to trigger molecular changes in breast cells, specifically the production of the growth factor protein RANKL, which can lead to cancer. Blocking and neutralizing RANKL by applying an antibody is an entirely new concept to prevent breast cancer and will be tested in women with BCRCA1/2 mutations by Widschwendter's team after further laboratory work.

These findings also create a window of opportunity to prevent breast and ovarian cancer in BRCA mutation carriers. After further laboratory work, the researchers anticipate that an existing drug that is currently used to treat osteoporosis could be suitable for use in a clinical trial of breast cancer prevention in BRCA1/2 mutation carriers.

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