1. The FA/BRCA pathway and breast cancer risk

1. Expanding the Fanconi anemia/breast cancer signaling pathwayThe Fanconi anemia/breast cancer signaling pathway plays a key role in the DNA damage response, which, in turn, may be altered in increased breast cancer risk. Genes with high-, moderate- or low-penetrance mutations for breast cancer and >15 Fanconi anemia genes (FANCs) encode for proteins of this pathway. In addition, modifiers of high-penetrance BRCA1/2 mutations are also components of the same pathway. Therefore, it is widely thought that additional genes in this pathway correspond to uncloned Fanconi anemia complementation groups and/or an unknown number of breast cancer genes. To gain a complete picture of this pathway and its link to disease, we have carried out protein-protein interaction screens for >50 components. These screens have identified several novel, high-confidence interaction partners, some of which are involved in biological processes such as cell cycle regulation and DNA damage response. Mutational and genotyping analyses are underway to define the potential role of these novel components in Fanconi anemia and/or breast cancer families without mutations in BRCA1/2.

2. Cell reprogramming and therapeutic resistance

2. Signaling rewiring and molecular mechanisms in acquired endocrine resistanceThe initial existence or posterior development of resistance to one or several anti-cancer treatments is certainly the most frequent cause of failure to cure of cancer patients. Despite major advances in understanding of the molecular basis of cancer obtained during recent years, there are very few examples of the translation of therapeutic strategies against resistance. This limitation is largely due to the lack of "integrated" models of resistance to the various standard drugs.

acWe have generated a collection of ortho-xenograft tumors in nude mice that are used for the study of the genetics of chemoresistance. Familial cases, and ER-negative and triple-negative primary or post-treatment tumors are engrafted in nuce mice and, subsequently, evaluated for their response in vivo to several compounds/drugs. The relapsing tumors are processed for exome sequencing and acquired mutations analysed in the original tissue sample and/or original xeonograft. Findings are validated prospectively.

3. Network modeling and breast cancer risk

3. Network modeling and breast cancer riskBreast cancer is a heterogeneous disease that may initiate at different points in the epithelial differentiation hierarchy. Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. We have recently described a molecular network containing AURKA, BRCA1, and RHAMM that regulates mammary epithelial apicobasal polarization. Functional alteration of network components may be at the basis of an increased risk of estrogen receptor α-negative breast cancer. We aim to further decipher the role of RHAMM in mammary epithelial differentiation and to evaluate the role of other breast cancer susceptibility gene products in this setting. To this end, we combine omic data analyses with experimental evaluations to identify genetic interactions influencing breast cancer risk. In addition, we perform systems-level studies of interactome and transcriptome data directed at defining the fundamental properties of cancer development and progression.

To this study centered on HMMR/RHAMM, we are expanding the potential collection of susceptibility genes/alleles through integrated analyses of GWAS and omic data, and genetic studies within the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).