Deep proteome profiling of human mammary epithelia at lineage and age resolution
Stefan Hinz,
Antigoni Manousopoulou,
Masaru Miyano,
Rosalyn W. Sayaman,
Kristina Y. Aguilera,
Michael E. Todhunter,
Jennifer C. Lopez,
Lydia L. Sohn,
Leo D. Wang,
Mark A. LaBarge
Affiliations
Stefan Hinz
Department of Population Sciences, Beckman Research Institute, Duarte, USA
Antigoni Manousopoulou
Departments of Pediatrics and ImmunoOncology, City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA
Masaru Miyano
Department of Population Sciences, Beckman Research Institute, Duarte, USA
Rosalyn W. Sayaman
Department of Population Sciences, Beckman Research Institute, Duarte, USA; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
Kristina Y. Aguilera
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
Michael E. Todhunter
Department of Population Sciences, Beckman Research Institute, Duarte, USA
Jennifer C. Lopez
Department of Population Sciences, Beckman Research Institute, Duarte, USA
Lydia L. Sohn
Department of Mechanical Engineering, University of California at Berkeley, Berkeley 94720-1740, USA
Leo D. Wang
Departments of Pediatrics and ImmunoOncology, City of Hope, 1500 E. Duarte Rd, Duarte, CA 91010, USA; Corresponding author
Mark A. LaBarge
Department of Population Sciences, Beckman Research Institute, Duarte, USA; Center for Cancer and Aging Research, Duarte, USA; Corresponding author
Summary: Age is the major risk factor in most carcinomas, yet little is known about how proteomes change with age in any human epithelium. We present comprehensive proteomes comprised of >9,000 total proteins and >15,000 phosphopeptides from normal primary human mammary epithelia at lineage resolution from ten women ranging in age from 19 to 68 years. Data were quality controlled and results were biologically validated with cell-based assays. Age-dependent protein signatures were identified using differential expression analyses and weighted protein co-expression network analyses. Upregulation of basal markers in luminal cells, including KRT14 and AXL, were a prominent consequence of aging. PEAK1 was identified as an age-dependent signaling kinase in luminal cells, which revealed a potential age-dependent vulnerability for targeted ablation. Correlation analyses between transcriptome and proteome revealed age-associated loss of proteostasis regulation. Age-dependent proteome changes in the breast epithelium identified heretofore unknown potential therapeutic targets for reducing breast cancer susceptibility.
