YAP1 dysfunction promotes molecular properties linked to breast cancer susceptibility

YAP1 is a co-transcription factor that promotes malignant and stem cell properties in cancer. We previously found that YAP1 dysregulation is associated with aging in human mammary epithelia. With increased age, YAP1 expression changes in luminal epithelial cells, the prospective breast cancer cell of origin. Because age is a significant risk factor for breast cancer, we tested if YAP1 dysregulation acted early in cancer progression by conferring cellular states associated with increased cancer susceptibility. Here we find, that with increased age and genetic risk for developing cancer, human breast tissues showed significantly increased YAP1 expression and cultured primary human mammary epithelial cells (HMEC) showed significantly increased expression of both YAP1 and its transcriptional targets. Increased YAP1 expression in cultured HMEC induced gene expression changes associated with increased cancer susceptibility such as genes associated with: a stem cell fate, cells with increased telomerase activity, breast cancer progression, and increased age and genetic breast cancer risk. Further, overexpression of YAP1 in post-stasis HMEC- finite lifespan cells which have bypassed a retinoblastoma-mediated senescence barrier- promoted properties related to an increased growth potential. We found that YAP1 dysregulation in finite post-stasis epithelial cells allows for access to gene programs and functions that are typically thought to be restricted to stem cells. We hypothesize that YAP1 acts early in breast cancer progression, before development of a tumor, to impose cancer susceptible molecular states.