Research in the Hill Lab
The BRCA1 tumor suppressor, along with its protein binding partners, is involved in a diverse array of functions ranging from participation in repair of DNA double strand breaks by homologous recombination to protection of stalled replication forks, amongst others (Hill and Livingston 2014; Hill and Livingston 2014; Hill and Livingston 2016; Yang and Hill 2024). Patients with BRCA1 mutations are highly susceptible to both triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSC), yet the key breast and ovarian tumor suppressing function of BRCA1 is not known. Broadly, our laboratory seeks to better understand the role of BRCA1 in breast and ovarian tumor suppression, tumor biology, and therapeutic sensitivity and resistance by addressing the following questions:
1) What is the role of BRCA1 protein complexes in DNA replication, in particular in regulating replication origins as part of the ORFIUS complex (Yang and Hill 2024)?
2) How do defects in the function of BRCA1 protein complexes lead to transformation of breast cancer precursor and fallopian tube or other HGSC precursor cells to pre-malignant and malignant states, and can we detect and possibly prevent malignant transformation? Also, how can such replication or DNA damage repair functional defects be therapeutically targeted in breast and ovarian cancers, in particular beyond PARP inhibition?
3) How does stressing functional defects in BRCA1 protein complexes within breast or ovarian tumor cells reshape the surrounding tumor microenvironment, and might there be relevant immune/DNA damage therapeutic combinations (Wan and Hill 2021)?
Additionally, although endometrial cancers do not commonly harbor mutations in BRCA1, our laboratory has discovered that many endometrial cancers do harbor targetable defects or proficiencies in controlling the cell cycle (Yang and Hill 2025). Thus, we are also addressing similar questions as above in endometrial cancers.
We utilize an array of models to address these questions including established cell lines, xenografts, syngeneic mouse models, and novel tumor/immune cell co-cultures pioneered in the Hill lab (Wan and Hill 2021). The co-cultures are generated from patient samples and contain matched immune, stromal, and tumor cells which allow us to study the response of every cell in a tumor to any therapy or perturbation. We utilize immunofluorescence microscopy, cell and molecular biology, DNA damage repair, flow cytometry, and various sequencing assays on these models to address the above questions.
The ultimate goal of the lab is to utilize our basic science understanding of the fundamental biology of BRCA1 and related complexes in tumor intrinsic DNA damage repair/replication functions, particularly in replication origin regulation, and linked tumor microenvironment functions to generate better methods of breast, ovarian, and endometrial cancer detection, prevention, and treatment.
1) What is the role of BRCA1 protein complexes in DNA replication, in particular in regulating replication origins as part of the ORFIUS complex (Yang and Hill 2024)?
2) How do defects in the function of BRCA1 protein complexes lead to transformation of breast cancer precursor and fallopian tube or other HGSC precursor cells to pre-malignant and malignant states, and can we detect and possibly prevent malignant transformation? Also, how can such replication or DNA damage repair functional defects be therapeutically targeted in breast and ovarian cancers, in particular beyond PARP inhibition?
3) How does stressing functional defects in BRCA1 protein complexes within breast or ovarian tumor cells reshape the surrounding tumor microenvironment, and might there be relevant immune/DNA damage therapeutic combinations (Wan and Hill 2021)?
Additionally, although endometrial cancers do not commonly harbor mutations in BRCA1, our laboratory has discovered that many endometrial cancers do harbor targetable defects or proficiencies in controlling the cell cycle (Yang and Hill 2025). Thus, we are also addressing similar questions as above in endometrial cancers.
We utilize an array of models to address these questions including established cell lines, xenografts, syngeneic mouse models, and novel tumor/immune cell co-cultures pioneered in the Hill lab (Wan and Hill 2021). The co-cultures are generated from patient samples and contain matched immune, stromal, and tumor cells which allow us to study the response of every cell in a tumor to any therapy or perturbation. We utilize immunofluorescence microscopy, cell and molecular biology, DNA damage repair, flow cytometry, and various sequencing assays on these models to address the above questions.
The ultimate goal of the lab is to utilize our basic science understanding of the fundamental biology of BRCA1 and related complexes in tumor intrinsic DNA damage repair/replication functions, particularly in replication origin regulation, and linked tumor microenvironment functions to generate better methods of breast, ovarian, and endometrial cancer detection, prevention, and treatment.
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©2019 Hill Lab at Dana-Farber Cancer Institute
©2019 Hill Lab at Dana-Farber Cancer Institute