New Models to Study Estrogen’s Role
in Breast Cancer

Estrogen signaling is an essential process for normal breast development but is also a key mechanism contributing to the development of breast cancer, making it a growing target of modern therapies. New studies are shedding light on the complex signaling mechanisms that separate benign estrogen receptor (ER) activity from that which drives late recurrence in breast cancer. This blog will delve into some of the latest research on estrogen’s dual role in normal breast development, carcinogenesis and opportunities for precision medicine.

Many of the results  reviewed here were recently reported at the Buenos Aires Breast Cancer Symposium¹, which brought together scientists and researchers from across the world to discuss the advancement of research and therapeutic strategies for breast cancer. This gathering of interdisciplinary researchers, facilitated conversation and understanding surrounding the mechanisms of ER signaling and how it contributes to breast cancer.

ILC and ER+ Breast Cancer Research
In a  2024 study, patients with estrogen-receptor positive (ER +) invasive lobular carcinoma (ILC) had significantly worse long-term disease-specific and overall survival rates than ER + no special type (NST), attributable to late recurrences.²  This difference in survival highlights the need to study ILC in more detail and develop specific treatments. These results found that a particular cell signaling pathway, cAMP/PKA/CREB, is more active in ILC than NST. When researchers tested this pathway in lab-grown ILC cells and tissue samples, they observed a stronger response to a pathway-activating drug, and ILC cells were more sensitive to the drug’s growth-inhibiting effects. This suggests that the cAMP/PKA/CREB pathway could be a promising target for new ILC treatments.

Understanding the broader context of estrogen signaling’s complex effects on breast cancer cells is crucial, and extends beyond this specific cAMP/PKA/CREB pathway. Germline mutations in BRCA1, BRCA2 and PALB2 can compromise DNA repair through homologous recombination and preferentially predispose to breast cancer. Among carriers of mutations in BRCA1/2, those with ER+ breast cancers typically have poorer survival compared to the ER-negative breast cancers.^{3 4}
This contrasts with the general population where ER+ is a biomarker of better prognosis. Several laboratories have shown that ER signaling can lead to DNA double-strand breaks in breast cancer cell lines independent of proliferation. In normal breast tissues, transcriptional responses to estrogen showed variable effects on target genes among individuals.⁵

A recent publication by Dr. Joseph Jerry, Director of Biorepository at HistoSpring, and his lab team used an inducible estrogen signaling system in normal breast epithelial cell lines to observe common transcriptional patterns among cells from four individuals. In doing so, they also observed “private patterns” of gene expression reflecting variation in the targets of ER signaling among individuals.⁶  Among observations, Dr. Jerry and his team found that estrogen signaling caused DNA damage, marked by an increase in γH2AX in most of these normal breast cell lines. Importantly, the number of DNA double-strand breaks caused by ER-signaling was increased in cells with heterozygous mutations in BRCA1. This suggests that having a BRCA1 mutation may make cells more vulnerable to DNA damage from estrogen as well as providing models that better represent the genetic and epigenetic diversity found among women. This research provides new tools to study how estrogen affects normal breast cells, a challenge because scientists usually rely on cancer cell lines which do not represent healthy tissue. These  approaches offer opportunities to identify mechanisms underlying the variable penetrance of inherited mutations in breast cancer susceptibility genes and support precision prevention strategies.

Therapeutic Implications and Model Development
Recent work from the Todd Miller Lab has also reported that pathogenic ER signaling damages DNA in breast cancer cells partly through the formation of R-loops. They exploited this to treat endocrine-resistant ER+ breast cancers.  High doses of estrogen were used to stimulate DNA breaks.  Blocking DNA repair with PARP inhibitors amplifies the damage, resulting in synergistic tumor growth suppression and cell death. Furthermore, the POLLY clinical trial demonstrated that alternating estrogen with aromatase inhibitors (AIs) in advanced estrogen-resistant ER+ breast cancer yielded a 42% clinical benefit rate, particularly in patients with mutations in the estrogen receptor. These results suggest that strategically using estrogen, either with PARP inhibitors or AIs, offers a promising therapeutic approach. Therefore, the genotoxic effect of pathogenic ER signaling can be harnessed to cause regression of breast tumors with higher doses of estrogen.⁷

These recent studies demonstrate the need for cell-based models to identify mechanisms that distinguish pathogenic ER signaling in breast cancers from normal estrogen signaling needed to maintain normal breast tissue. This ignited efforts to develop methods to extend the in vitro lifespan breast epithelial cells.
Co-expression of CDK4 and TERT provided a robust strategy to maintain breast cells from genetically diverse donors.¹ These methods can be used to reconstruct ER signaling using the inducible system reported by Majhi and co-workers.⁶

These findings present invaluable tools for identifying key mechanisms of estrogen signaling contributing to breast oncogenesis. Dr. Jerry and his lab team continue to advance research by focusing on mechanisms regulating risk and resistance to breast cancer.