Sarah Hill

The BRCA1 tumor suppressor along with its protein binding partners is involved in a diverse array of DNA damage repair functions ranging from participation in repair of DNA double strand breaks to protection of stalled replication forks. Women with BRCA1 mutations are highly susceptible to both breast and ovarian cancer, yet the key tumor suppressing function of BRCA1 remains ill-defined. Broadly, our laboratory seeks to better understand the role of BRCA1 in breast and ovarian tumor suppression 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 preventing replication fork slowing/stalling and also in dealing with the consequences thereof? 
2) How do defects in the function of BRCA1 protein complexes lead to transformation of breast and fallopian tube 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? 

Additionally, although endometrial cancers do not often harbor mutations in BRCA1, our laboratory has discovered that many endometrial cancers also harbor defects in 1) preventing replication fork slowing/stalling, or 2) properly arresting the cell cycle to deal with the consequences of such replication defects. Thus, we are also addressing similar questions as above in sporadic endometrial cancers.

We utilize an array of model systems to address these questions including established cell lines, patient-derived organoid models, xenografts, syngeneic mouse models, and novel organoid/immune cell co-cultures pioneered in the Hill lab. The organoid co-cultures are generated from patient samples directly from the operating room 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, proteomics, ELISA, flow cytometry, and single cell RNA 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 and linked tumor microenvironment functions to generate better methods of breast, ovarian, and endometrial cancer detection, prevention, and treatment.