Abstract BL2: The Molecular Etiology of Luminal-Type Breast Cancer

Abstract

Abstract Estrogen receptor positive disease is the dominant contributor to global deaths from breast cancer which now exceeds 500,000 deaths annually. Lethality is driven by endocrine therapy resistance, the development of metastasis and an inability of the immune system to mount an effective anti-tumor T cell response. While our understanding of these processes is incomplete, molecular analyses of ER+ tumor samples accrued from patients undergoing neoadjuvant endocrine therapy (NET) have generated fundamental insights into nature of the disease while providing clear benefits to patients in terms of increased use of breast conserving surgery and strategies to avoid chemotherapy1,2. From the outset, genomic analyses of ER+ breast cancer samples has demonstrated that poor outcome is associated with genomic complexity and sub-clonal diversity3,4. As endocrine therapy responsive tumors are exposed to treatment, responsive subclones regress and resistant subclones expand. Eventually clones harboring lethal mutations are selected, including ER ligand binding mutations and chromosomal translocations involving ER that generate EMT-driving chimeric transcription factors5,6. Additional genomic events include loss of tumor suppressors that deregulate ER function, such as NF1 frame-shift or nonsense mutations7, or gain of function mutations in growth factor receptors such as ErbB28. These acquired resistance mutations are druggable and targeted interventions should prove useful. But what are the DNA repair defects that underlie the lethal genomic complexity of ER+ disease? Unlike ER negative/basal like breast cancer, luminal-type breast cancer is typically not defective in homologous recombination and is TP53 wild-type. Our recent data suggest loss of components in single strand (ss) DNA repair mechanisms associate with poor prognosis in ER+ breast cancer including MLH1/PMS1/PMS2 (mismatch repair), NEIL2 (base excision repair) or ERCC1 (nucleotide excision repair)9,10. Experimental down-regulation of any of these five genes generates endocrine therapy resistance, likely by disrupting CHK2 signaling, which acts as an endogenous inhibitor of CDK4/6 function. Indeed, direct CHK2 knockdown also generates endocrine therapy resistance but CDK4/6 inhibitor sensitivity is maintained in all these experimental conditions. Essentially the CDK4/6 inhibitor therapy can be seen as replacing CHK2 for negative cell cycle regulation. Thus, we postulate that the presence of ssDNA break repair defects and/or CHK2 dysregulation could underlie the remarkably selective efficacy of CDK4/6 inhibitors in ER+ disease by targeting the intersection of ER signaling and the ssDNA repair response at the level of CHK2 activity. Furthermore, correlations between poor prognosis in ER+ disease, increased innate immunity signaling and ssDNA repair defects point towards subsets of ER+ breast cancers that might respond to immune checkpoint therapy11.