Gertz Lab Research
Gertz Lab Research
Steroid hormones and their receptors play large roles in many tissues and biological processes. This includes the control of growth and differentiation, making steroid hormone receptors effective drug targets for cancer treatment. Our research goal is to improve the treatment of hormone-related cancers, including endometrial cancer and breast cancer, through a better understanding of how steroid hormone receptors regulate gene expression, which proteins control their activity, and how they work together. To determine how steroid hormones impact endometrial and breast cancers, we use and develop experimental methods that take advantage of high-throughput sequencing to create fine resolution maps of gene regulation. We also use cutting-edge computational approaches to take full advantage of these rich genomic datasets. An improved understanding of steroid hormones in cancer promises to uncover new therapeutic options for cancer patients and to identify which patients would most benefit from hormone therapy.
Control of estrogen receptor activity in endometrial cancer
Estrogen receptor alpha (ER) is an oncogenic transcription factor active in both breast and endometrial cancers. ER signaling pathways are complex and involve many different nuclear factors that control ER’s activity. Several of these factors have been identified in breast cancer, but few have been identified in endometrial cancer. We aim to discover these factors using a combination of machine learning, genomics, and CRISPR approaches in order to better understand endometrial cancer development and progression at the molecular level. The factors that we identify represent candidate drug targets for further exploration in endometrial cancer.
Estrogen and progesterone crosstalk in endometrial cancer
Estrogen and progesterone exert opposing effects on the endometrium: estrogen and its receptor, ER, promote epithelial proliferation, while progesterone and its receptor, progesterone receptor (PR), induce differentiation and suppress estrogen-driven growth. In breast cancer, active PR redirects ER to alternative genomic sites, disrupting ER activity at ER target genes. However, the nature of ER-PR interactions in endometrial cancer remains poorly understood. To address this, we use multi-omics approaches to understand how cells molecularly respond to estrogen and progesterone in isolation and in combination. By performing RNA-seq for transcriptional profiling and ChIP-seq for mapping ER and PR binding, we aim to uncover how PR modulates ER genomic activity and target gene expression. Our goal is to determine the molecular basis of progesterone’s antagonistic effects on estrogen signaling in endometrial cancer, which will offer insights into therapeutic interventions that improve endometrial cancer outcomes.
Improving progestin therapy use in endometrial cancer
Progestins, synthetic forms of progesterone, have been used since the 1970s to treat hormone-responsive endometrial cancer, primarily in patients seeking to maintain the ability to have children. However, clinical response is often temporary, and relapse is common. The lack of biomarkers that predict progestin response limits broader and more effective use of progestin therapy. We aim to define the molecular mechanisms by which progestins exert anti-tumor effects via PR. Using endometrial cancer cell lines and patient-derived samples, we investigate PR’s genomic and transcriptional activity, its downstream signaling effects, and associated phenotypic changes. Through integrative molecular profiling, we seek to identify RNA-based biomarkers and signaling pathways that predict therapeutic response. This work will inform more personalized use of progestins in endometrial cancer patients and may help to expand their application beyond current clinical limitations.
BAF complex alterations in endometrial cancer
While most endometrial cancers are driven by estrogen signaling, excess estrogen alone is not sufficient to promote disease. Nearly all endometrial tumors harbor mutations in at least one cancer-associated gene, suggesting that the combination of these genetic events and ER activity drives tumorigenesis. We are particularly interested in mutations in the multi-subunit BAF nucleosome remodeling complex, which is frequently altered in estrogen-dependent endometrial cancers. To explore how crosstalk between chromatin remodeling and estrogen signaling promotes cancer, we employ a variety of experimental and computational approaches aimed at answering: (1) How do mutations in BAF affect estrogen-regulated genes, and (2) What are the functional links between BAF and ER that enable healthy cells to become malignant? By developing a better understanding of the molecular connections and consequences between chromatin state and estrogen signaling, we hope to reveal novel therapeutic vulnerabilities to specifically target endometrial tumors that rely on these dependencies.
