Effect of conditional knockout of the type II TGF-beta receptor gene in mammary epithelia on mammary gland development and polyomavirus middle T antigen induced tumor formation and metastasis.
Transforming growth factor-beta (TGF-beta) isoforms are growth factors that function physiologically to regulate development, cellular proliferation, and immune responses. The role of TGF-beta signaling in mammary tumorigenesis is complex, as TGF-beta has been reported to function as both a tumor suppressor and tumor promoter. To elucidate the role of TGF-beta signaling in mammary gland development, tumorigenesis, and metastasis, the gene encoding type II TGF-beta receptor, Tgfbr2, was conditionally deleted in the mammary epithelium (Tgfbr2MGKO). Loss of Tgfbr2 in the mammary epithelium results in lobular-alveolar hyperplasia in the developing mammary gland and increased apoptosis. Tgfbr2MGKO mice were mated to the mouse mammary tumor virus-polyomavirus middle T antigen (PyVmT) transgenic mouse model of metastatic breast cancer. Loss of Tgfbr2 in the context of PyVmT expression results in a shortened median tumor latency and an increased formation of pulmonary metastases. Thus, our studies support a tumor-suppressive role for epithelial TGF-beta signaling in mammary gland tumorigenesis and show that pulmonary metastases can occur and are even enhanced in the absence of TGF-beta signaling in the carcinoma cells.
Forrester
Elizabeth
E
Department of Cancer Biology, Ingram Cancer Center, Nashville, Tennessee, USA.
Chytil
Anna
A
Bierie
Brian
B
Aakre
Mary
M
Gorska
Agnieszka E
AE
Sharif-Afshar
Ali-Reza
AR
Muller
William J
WJ
Moses
Harold L
HL
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D005260:Female; D006965:Hyperplasia; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary; D008297:Male; D008321:Mammary Glands, Animal / Q000254:growth & development / Q000378:metabolism / Q000502:physiology*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases; D011650:Pulmonary Alveoli / Q000473:pathology; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics*; D019076:Transgenes / Q000235:genetics
D000952:Antigens, Polyomavirus Transforming; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II