Lack of fetuin-A (alpha2-HS-glycoprotein) reduces mammary tumor incidence and prolongs tumor latency via the transforming growth factor-beta signaling pathway in a mouse model of breast cancer.
The present analyses were done to define the role of fetuin-A (Fet) in mammary tumorigenesis using the polyoma middle T antigen (PyMT) transgenic mouse model. We crossed Fet-null mice in the C57BL/6 background with PyMT mice in the same background and after a controlled breeding protocol obtained PyMT/Fet+/+, PyMT/Fet+/-, and PyMT/Fet-/- mice that were placed in control and experimental groups. Whereas the control group (PyMT/Fet+/+) formed mammary tumors 90 days after birth, tumor latency was prolonged in the PyMT/Fet-/- and PyMT/Fet+/- mice. The majority of the PyMT/Fet-/- mice were tumor-free at the end of the study, at approximately 40 weeks. The pathology of the mammary tumors in the Fet-null mice showed extensive fibrosis, necrosis, and squamous metaplasia. The preneoplastic mammary tissues of the PyMT/Fet-/- mice showed intense phopho-Smad2/3 staining relative to control tissues, indicating that transforming growth factor-β signaling is enhanced in these tissues in the absence of Fet. Likewise, p19ARF and p53 were highly expressed in tumor tissues of PyMT/Fet-/- mice relative to the controls in the absence of Fet. The phosphatidylinositol 3-kinase/Akt signaling pathway that we previously showed to be activated by Fet, on the other hand, was unaffected by the absence of Fet. The data indicate that Fet is a powerful modulator of breast tumorigenesis in this model system and has the potential to modulate breast cancer progression in humans.
Guillory
Bobby
B
Department of Biochemistry and Cancer Biology, Meharry Medical College, 1005 D.B. Todd Blvd., Nashville, TN 37208, USA.
Sakwe
Amos M
AM
Saria
Margret
M
Thompson
Pamela
P
Adhiambo
Christine
C
Koumangoye
Rainelli
R
Ballard
Billy
B
Binhazim
Awadh
A
Cone
Cecil
C
Jahanen-Dechent
Willi
W
Ochieng
Josiah
J
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000378:metabolism; D001798:Blood Proteins / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000453:epidemiology* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000453:epidemiology* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D060749:alpha-2-HS-Glycoprotein
C556354:AHSG protein, human; C556357:Ahsg protein, mouse; D000952:Antigens, Polyomavirus Transforming; D001798:Blood Proteins; D016212:Transforming Growth Factor beta; D060749:alpha-2-HS-Glycoprotein; D058539:Phosphatidylinositol 3-Kinase