title: The milk protein α-casein functions as a tumor suppressor via activation of STAT1 signaling, effectively preventing breast cancer tumor growth and metastasis.
abstract: Here, we identified the milk protein α-casein as a novel suppressor of tumor growth and metastasis. Briefly, Met-1 mammary tumor cells expressing α-casein showed a ~5-fold reduction in tumor growth and a near 10-fold decrease in experimental metastasis. To identify the molecular mechanism(s), we performed genome-wide transcriptional profiling. Interestingly, our results show that α-casein upregulates gene transcripts associated with interferon/STAT1 signaling and downregulates genes associated with "stemness." These findings were validated by immunoblot and FACS analysis, which showed the upregulation and hyperactivation of STAT1 and a decrease in the number of CD44(+) "cancer stem cells." These gene signatures were also able to predict clinical outcome in human breast cancer patients. Thus, we conclude that a lactation-based therapeutic strategy using recombinant α-casein would provide a more natural and non-toxic approach to the development of novel anticancer therapies.
authors.affiliation: The Jefferson Stem Cell Biology and Regenerative Medicine Center, Department of Stem Cell Biology & Regenerative Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Gloria
authors.initials: G
authors.lastname: Bonuccelli
authors.forename: Remedios
authors.initials: R
authors.lastname: Castello-Cros
authors.forename: Franco
authors.initials: F
authors.lastname: Capozza
authors.forename: Ubaldo E
authors.initials: UE
authors.lastname: Martinez-Outschoorn
authors.forename: Zhao
authors.initials: Z
authors.lastname: Lin
authors.forename: Aristotelis
authors.initials: A
authors.lastname: Tsirigos
authors.forename: Jiao
authors.initials: J
authors.lastname: Xuanmao
authors.forename: Diana
authors.initials: D
authors.lastname: Whitaker-Menezes
authors.forename: Anthony
authors.initials: A
authors.lastname: Howell
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.forename: Federica
authors.initials: F
authors.lastname: Sotgia
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D002364:Caseins / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007372:Interferons / Q000378:metabolism; D051379:Mice; D008895:Milk, Human; D014411:Neoplastic Stem Cells / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation
chemical_list: D002364:Caseins; D018960:Hyaluronan Receptors; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D007372:Interferons