title: Tumor microenvironment-derived proteins dominate the plasma proteome response during breast cancer induction and progression.
abstract: Tumor development relies upon essential contributions from the tumor microenvironment and host immune alterations. These contributions may inform the plasma proteome in a manner that could be exploited for cancer diagnosis and prognosis. In this study, we employed a systems biology approach to characterize the plasma proteome response in the inducible HER2/neu mouse model of breast cancer during tumor induction, progression, and regression. Mass spectrometry data derived from approximately 1.6 million spectra identified protein networks involved in wound healing, microenvironment, and metabolism that coordinately changed during tumor development. The observed alterations developed prior to cancer detection, increased progressively with tumor growth and reverted toward baseline with tumor regression. Gene expression and immunohistochemical analyses suggested that the cancer-associated plasma proteome was derived from transcriptional responses in the noncancerous host tissues as well as the developing tumor. The proteomic signature was distinct from a nonspecific response to inflammation. Overall, the developing tumor simultaneously engaged a number of innate physiologic processes, including wound repair, immune response, coagulation and complement cascades, tissue remodeling, and metabolic homeostasis that were all detectable in plasma. Our findings offer an integrated view of tumor development relevant to plasma-based strategies to detect and diagnose cancer.
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Pitteri
authors.forename: Karen S
authors.initials: KS
authors.lastname: Kelly-Spratt
authors.forename: Kay E
authors.initials: KE
authors.lastname: Gurley
authors.forename: Jacob
authors.initials: J
authors.lastname: Kennedy
authors.forename: Tina Busald
authors.initials: TB
authors.lastname: Buson
authors.forename: Alice
authors.initials: A
authors.lastname: Chin
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Chee-Hong
authors.initials: CH
authors.lastname: Wong
authors.forename: Lewis A
authors.initials: LA
authors.lastname: Chodosh
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.forename: Samir M
authors.initials: SM
authors.lastname: Hanash
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kemp
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000032:analysis*; D001943:Breast Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor / Q000737:chemistry; D018450:Disease Progression; D004318:Doxycycline / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000097:blood* / Q000235:genetics / Q000473:pathology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000032:analysis; D020543:Proteome; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D019076:Transgenes; D059016:Tumor Microenvironment / Q000502:physiology*
chemical_list: D001798:Blood Proteins; D004318:Doxycycline; D009363:Neoplasm Proteins; D020543:Proteome; D018719:Erb-b2 Receptor Tyrosine Kinases; C483804:Erbb2 protein, rat