BRCANCER · A novel approach for modeling development of breast cancer

A novel approach for modeling development of breast cancer

Inheriting one mutant copy of the BReast CAncer 1 (BRCA1) or BRCA2 gene is linked to a significant increased risk of developing breast, ovarian and other cancers. BRCA1 and BRCA2 mutations account for about 5 to 10 percent of all breast cancers, the most common cancer type in the women worldwide. BRCA1 is involved in various pathways essential for genomic maintenance such as the DNA damage response, X-chromosome inactivation, and cell cycle control. BRCA2 function is largely restricted to DNA recombination and repair processes. Genomic instability caused by loss-of-function mutations in BRCA1 or BRCA2 probably underlies the cancer predisposition, however, the critical mechanisms by which loss or mutagenesis of BRCA1 or BRCA2 leads to tumorigenesis remain unclear. Of the six major breast tumor subtypes, familiar BRCA1 mutant tumors segregate strongly with basal-like cancers and are among the most aggressive. Basal-like tumors account for ~20% of breast cancers and are characterized by triple negativity for estrogen receptor (ER), progesterone receptor (PR) and the human epidermal growth factor receptor 2 (HER2). The absence of ER and HER2 expression precludes the use of endocrine therapy or anti-HER2 treatment and limits systemic treatment to cytotoxic chemotherapy1. For both BRCA1- and BRCA2-dependent cancers, the efficacy of treatments greatly varies between individuals. Together, it highlights the need for development of novel biomarkers, treatment strategies and personalized medicine approaches for breast cancer. The objectives for the outgoing phase are: 1. To define the sequence of tumor suppressor gene mutations required to induce breast cancer 2. To identify molecular pathways and genetic profiles affected during BRCA1- or BRCA2- dependent breast cancer development The objectives for the return phase are: 1. To establish relations between in vitro breast tumor organoids, in vivo human-in-mouse xenografts and the original tumor 2. To characterize drug responsiveness of breast tumor organoids derived from different individuals To address these objectives, I will make use of state-of-the-art breast organoid cultures, CRISPR/Cas9-mediated gene editing and human-in-mouse xenografts (see Table 1 for a detailed explanation of these methodologies). Conclusions - It is feasible transform normal cells into tumor cells by knocking out the tumor suppressor genes P53, PTEN and RB - P53/PTEN/RB-KO lines have increased growth properties in vitro as compared to non-transformed cells - the clonal diversity during tumor progression in vivo is similar to the clonal diversity in in vitro organoids where tumors originated from - Both in vivo tumors and in vitro organoids respond to drug treatment

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