The risk of developing estrogen receptor (ER)-positive breast cancer increases in post-menopausal women if the gene Esr1 (estrogen receptor 1) is expressed excessively in glandular cells of the breasts, reports a study from the Georgetown Lombardi Comprehensive Cancer Center published in the American Journal of Pathology. Another study by the same group, in the same issue of the journal, reports preclinical evidence that administration of anti-hormonal drugs such as tamoxifen and letrozole, can reduce the risk of developing breast cancer due to overexpression of Esr1. The studies use a new mouse model of aging that mimics breast cancer development in ER-positive post-menopausal women.

“In the clinic, we currently use tests for overexpression of particular patterns of genes to predict the probability of whether a woman’s breast cancer could become metastatic,” said Priscilla Furth, MD, professor of oncology and medicine at Georgetown Lombardi and senior author of both studies. “If validated in human studies, detection of overexpression of Esr1-related genes could be a new signature to add to current prognostic tools that would help post-menopausal women at risk for estrogen receptor-positive breast cancer decide what their best risk reduction strategy might be.”

Overexpression of Esr1 and consequent increase in components of the estrogen pathway trigger a significant fraction of breast cancers in post-menopausal women. When overall estrogen levels decline during menopause, in some women, cells in the breast step up local production of the estrogen receptor and estrogen.

In the first study, the investigators analyzed breast cancers in aged mice with typically declining blood estrogen levels, that overexpressed either Esr1 or CYP19A1, an aromatase enzyme that converts androgens to various forms of estrogen. The researchers found that Esr1 overexpression led to more breast cancers than CYP19A1 overexpression and was accompanied by excessive activation of genes in the estrogen pathway. In the second study, the researchers administered estrogen-suppressive drugs (tamoxifen and letrozole) to the mice and noted that these drugs prevented the abnormal activation of genes in the estrogen pathway.

The PAM50 (Prediction Analysis of Microarray 50) prognostic test that the researchers used in the study, determines expression levels of 50 genes in each tumor sample. Most genes related to proliferation of breast cancer cells detected using this test were significantly expressed in only Esr1 overexpressing mice. This correlates with the development of ER-positive breast cancers in humans, providing insights on new genes that might be involved in triggering breast cancer in post-menopausal women.

“One of the more important challenges in translating our findings from mice to people is the collection of breast cancer cells for testing with PAM50 or other prognostic tools,” said Furth. “Removing breast tissue, even with a fine needle, is still invasive and perhaps unavoidable. However, we have developed a method in my lab that requires collecting just a few tumor cells from a small tissue sample, as our process expands and grows the cells many-fold so that we can have adequate cancer cell numbers to run through prognostic tools like PAM50.”

Furth and her colleagues hope the current findings will induce researchers and developers of diagnostic tools to incorporate Esr1-linked genes in their assays.

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