Researchers at Georgetown Lombardi Comprehensive Cancer Center and colleagues found that over-expression, or switching on, of the Esr1 gene could increase the risk of developing estrogen receptor-positive breast cancer in older women. The study used a first-of-its-kind mouse model of aging that mimics breast cancer development in post-menopausal women with estrogen receptor positivity.
In a subsequent study from the same research lab, researchers discovered that the increased risk of developing breast cancer caused by Esr1 over-expression could be reduced or reversed in specially bred mice given anti-hormonal drugs (such as tamoxifen and letrozole), similar to those currently used by women to reduce their risk of developing breast cancer.
According to Priscilla Furth, M.D., professor of oncology and medicine at Georgetown Lombardi and corresponding author of both studies, “In the clinic, we currently use tests for the over-expression of specific patterns of genes to predict the likelihood that a woman’s breast cancer could become metastatic.” “Detection of over-expression 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,” says the study. “If validated in human studies.”
The majority of women begin menopause in their late 40s or early 50s, and the chance of developing breast cancer increases with age, reaching its highest point around 70. Over-expression of the Esr1 gene contributes to a significant fraction of these breast cancers by increasing the expression of genes involved in the estrogen pathway, which in turn promotes the growth of breast cancer.
Some women’s breast tissue may exhibit an increase in estrogen receptor expression or possibly an increase in local estrogen synthesis during human menopause, while overall estrogen levels normally fall. The researchers observed the mice as they matured through their natural reproductive cycle and lowered amounts of circulating estrogen in order to model this in mice. They next compared results in mice engineered to overexpress either Esr1, which would simulate the increase in estrogen receptor levels, or CYP19A1, which would model the increase in local estrogen production, to discover what factors were involved in the malignancies that resulted. They discovered that Esr1 over-expression increased estrogen pathway gene activation and caused more breast tumors than CYP19A1 over-expression.
In the second trial, estrogen-suppressive medications like tamoxifen and letrozole were administered to the mice as a preventive step to test if the medications could resolve aberrant activation of the estrogen pathway genes, which it turned out they could.
Utilizing the PAM50 (Prediction Analysis of Microarray 50) prognostic tool helped the researchers in their investigation. The instrument analyzes a tumor sample and calculates the expression levels of 50 genes. The discovery by the researchers that many genes associated with the growth of breast cancer cells in the PAM50 tool were significantly expressed only in Esr1 mice and that this expression was correlated with the development of the same type of estrogen receptor-positive breast cancers that develop in humans provided them with new evidence regarding which other genes may be responsible for causing breast cancer in post-menopausal women. PAM50 test findings have been used to predict the likelihood of metastasis in some ER-positive, HER2-negative breast tumors in current clinical practice.
The collecting of breast cancer cells for testing with PAM50 or other prognostic tools is one of the more significant difficulties in applying our findings from mice to humans, according to Furth. “Even with a tiny needle, removing breast tissue is invasive and might not be prevented.” However, my lab has created a technique that only needs a minimal number of tumor cells to be removed from a sample of tissue since our technology multiplies the cells many times so that we have enough cancer cells to run through prognostic software like PAM50.
The researchers are hoping that other researchers, including those who develop commercial prognostic tools, will take note of this research advance and include risk factors connected to some of the genes linked to Esr1 in their tools, possibly enabling women to better avoid overtreatment or choose more accurate treatments.
