Genetic Modifiers of Initiation and Progression of Mammary Cancer

Division Of Basic Sciences - Nci

Investigators

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Abstract

Breast cancer remains the most commonly diagnosed malignancy and is the second leading cause of cancer-related death in American women. It is estimated that there were more than 266,000 new cases of breast cancer in the United States in 2018, with 41,000 patients succumbing to the disease. Although the 5-year survival approaches 100% for those patients diagnosed with localized disease, the 5-year survival rate for patients diagnosed with distant metastatic disease in only 27%, highlighting the critical importance of the metastatic process in patient mortality. For those patients diagnosed with localized disease, the widespread application of adjuvant chemotherapy has reduced late relapse and long-term mortality by an estimated 19%. However, despite these efforts, 25% of patients receiving adjuvant chemotherapy still progress to metastatic disease. Despite changes in therapeutic strategies little improvement in the survival of these patients has been observed . At present it is estimated that 155,000 women are currently living with metastatic disease in the United States, highlighting the significant public health burden of this disease. It is therefore critically important to obtain a comprehensive understanding of the etiology and biology of metastases to develop more effective clinical interventions to further reduce the morbidity and mortality of advanced breast cancer. In FY22 we have performed two parallel strategies for further investigations into the etiology of breast cancer metastasis. The first strategy investigated the acquisition of somatic mutations and copy number variations that might function as driver mutations for metastatic progression. Extending our previous analysis in the MMTV-PyMT mouse model, we have added additional primary-metastasis pairs to our data set, as well as analyzing three additional models of metastatic mammary cancer, MMTV-Myc, MMTV-Her2 and C3(1)-TAg. Surprisingly, unlike the in primary tumor transformation, activation mutations enriched in metastases, induced by single nucleotide variants (SNVs), were relatively rare suggesting that point mutations are not a major driver of tumor progression. In contrast, recurrent copy number variations (CNVs) were frequently enriched metastases compared to primary tumors in a genotype-specific manner, suggesting that genomic instability may be the primary somatic driver of metastatic disease. Despite these recurrent CNVs, however, RNAseq revealed little transcriptional variation between matched primary and metastatic lesions. These data imply that transient interactions and cellular responses may be more important in metastatic progression than the stable differences, and that genomic instability may be required to enable cellular plasticity during the multiple cellular insults and challenges faced during the metastatic cascade. The second strategy pursued is the continuation of our genetic studies into the etiology of metastasis susceptibility. In FY2022 we published the results of a study of the role of the nuclear pore protein, NUP210, in metastatic progression. These studies demonstrated that NUP210 mediates mechanical signaling from the extracellular environment to poised promoters of migration and invasion genes, inducing tumor dissemination from the primary tumor mass. Intriguingly, proteomics analysis has revealed that additional, previously identified, metastasis susceptibility genes also participate in this mechanical response mechanism. The convergence of these independently identified metastasis-associated factors on a single multiprotein complex suggests that our genetic strategy is interrogating a critical component of the metastatic cascade. Importantly, these genes are not frequently mutated in either experimental model systems of metastasis nor in human clinical samples. Thus, our gene susceptibility screen appears to be highlighting important cellular and molecular mechanisms that would be difficult to access by conventional cancer research strategies. Current efforts are focused on more detailed analysis of the mechanisms and potential integration of additional metastasis susceptibility genes that may contribute to the tumor dissemination mechanotransduction response.