Mihriban Karaayvaz Laboratory

Research

Overview

Our laboratory focuses on understanding the early events in breast cancer development. Our research begins in the clinic, with the analysis of patient samples.We develop hypotheses based on our observations, and build experimental models to test these hypotheses with the goal of translating our findings into clinical care.Two of our main research focuses can be found below.

Consequences of BRCA1/2 haploinsufficiency

Individuals with germline heterozygous mutations in the breast cancer susceptibility genes BRCA1 or BRCA2 have a 70% lifetime risk of developing breast cancer, yet the mechanisms of these cancers remain largely unknown. There is growing evidence that BRCA1 and BRCA2 heterozygosity confers haploinsufficiency in normal human mammary epithelial cells for their multiple known functions. A major focus of the Karaayvaz lab is to determine the cellular effects of this BRCA1/2 haploinsufficiency in human breast epithelial cells.

BRCA1 haploinsufficiency leads to defects in normal mammary epithelial progenitor differentiation and to replication stress suppression in primary cells. Haploinsufficiency for BRCA1 also causes cell-type specific genomic instability and premature senescence.

There is relatively less research on understanding the role of haploinsufficiency for BRCA2 in normal human mammary epithelial cells. It has been reported that haploinsufficiency for BRCA2 leads to genomic instability via unscheduled R-loops. Our work demonstrated that BRCA2 haploinsufficiency and associated DNA damage precede histologic abnormalities in BRCA2 mutation carriers. We discovered that single cells isolated from normal breast tissues of patients who carry germline truncating mutations affecting BRCA2, harbor frequent sub-chromosomal copy number variations (CNVs) (Science Advances, 2020). Correspondingly, these cells also exhibit attenuated DNA damage and apoptotic responses. 

Role of microenvironment in cancer-predisposed human breast tissues

Defects in mammary epithelial cell differentiation are present in BRCA1/2 mutation carriers even before cancer incidence. However, the underlying mechanism is largely unknown. Currently, we are investigating the influence of discovered receptor-ligand interactions on mammary epithelial cell differentiation using patient-derived experimental models that we are building in our lab. 

Cell fate decisions are driven by changes in environmental signals. Thus, we performed spatial transcriptomics using breast tissues from BRCA1/2 mutation carriers and from non-mutation carrier controls to study defects in mammary epithelial cell differentiation accompanied by unique microenvironmental alterations. We uncovered spatially defined receptor-ligand interactions in these tissues for the investigation of autocrine and paracrine signaling. We revealed both differences and similarities in the communication between mammary epithelial cells and the microenvironment in BRCA1 and BRCA2 mutation carriers (bioRxiv, 2023). 

Selected Publications

View publications for Mihriban Karaayvaz, PhD
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