ErbB3 is required for ductal morphogenesis in the mouse mammary gland.
BACKGROUND
The receptor ErbB3/HER3 is often over-expressed in human breast cancers, frequently in conjunction with over-expression of the proto-oncogene ERBB2/HER2/NEU. Although the prognostic/predictive value of ErbB3 expression in breast cancer is unclear, ErbB3 is known to contribute to therapeutic resistance. Understanding ErbB3 functions in the normal mammary gland will help to explain its role in cancer etiology and as a modulator of signaling responses to the mammary oncogene ERBB2.


METHODS
To investigate the roles of ErbB3 in mouse mammary gland development, we transplanted mammary buds from ErbB3-/- embryos into the cleared mammary fat pads of wild-type immunocompromised mice. Effects on ductal outgrowth were analyzed at 4 weeks, 7 weeks and 20 weeks after transplantation for total ductal outgrowth, branch density, and number and area of terminal end buds. Sections of glands containing terminal end buds were analyzed for number and epithelial area of terminal end buds. Terminal end buds were also analyzed for presence of mitotic figures, apoptotic figures, BrdU incorporation, and expression of E-cadherin, P-cadherin, alpha-smooth muscle actin, and cleaved caspase-3.


RESULTS
The mammary ductal trees developed from ErbB3-/- buds only partly filled the mammary fat pad. In contrast to similar experiments with ErbB2-/- mammary buds, this phenotype was maintained through adulthood, pregnancy, and parturition. In addition, and in contrast to similar work with ErbB4-/- mammary buds, lobuloalveolar development of ErbB3-/- transplanted glands was normal. The ErbB3-/- mammary outgrowth defect was associated with a decrease in the size of the terminal end buds, and with increases in branch density, in the number of terminal end buds, and in the number of luminal spaces. Proliferation rates were not affected by the lack of ErbB3, but there was an increase in apoptosis in ErbB3-/- terminal end buds.


CONCLUSIONS
Endogenous ErbB3 regulates morphogenesis of mammary epithelium.
Jackson-Fisher
Amy J
AJ
Department of Pathology, Yale School of Medicine, New Haven, CT 06520-8023, USA.
Bellinger
Gary
G
Breindel
Jerrica L
JL
Tavassoli
Fatteneh A
FA
Booth
Carmen J
CJ
Duong
James K
JK
Stern
David F
DF
D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001973:Bromodeoxyuridine; D015820:Cadherins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation; D004848:Epithelium; D005260:Female; D008321:Mammary Glands, Animal / Q000254:growth & development* / Q000378:metabolism / Q000637:transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009024:Morphogenesis; D009130:Muscle, Smooth / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D020893:Receptor, ErbB-3 / Q000502:physiology*
D000199:Actins; D015820:Cadherins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D020893:Receptor, ErbB-3; C505409:Casp3 protein, mouse; D053148:Caspase 3; D001973:Bromodeoxyuridine