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Molecular and Cellular Biology, June 2005, p. 4591-4601, Vol. 25, No. 11
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.11.4591-4601.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Bim Regulation of Lumen Formation in Cultured Mammary Epithelial Acini Is Targeted by Oncogenes

Mauricio J. Reginato ,1,{dagger},{ddagger} Kenna R. Mills,1,{dagger} Esther B. E. Becker,2 Danielle K. Lynch,1 Azad Bonni,2 Senthil K. Muthuswamy,1,§ and Joan S. Brugge1*

Department of Cell Biology,1 Department of Pathology, Harvard Medical School, Boston, Massachusetts 021152

Received 3 November 2004/ Returned for modification 2 December 2004/ Accepted 6 February 2005

Epithelial cells organize into cyst-like structures that contain a spherical monolayer of cells that enclose a central lumen. Using a three-dimensional basement membrane culture model in which mammary epithelial cells form hollow, acinus-like structures, we previously demonstrated that lumen formation is achieved, in part, through apoptosis of centrally localized cells. We demonstrate that the proapoptotic protein Bim may selectively trigger apoptosis of the centrally localized acinar cells, leading to temporally controlled lumen formation. Bim is not detectable during early stages of three-dimensional mammary acinar morphogenesis and is then highly upregulated in all cells of acini, coincident with detection of apoptosis in the centrally localized acinar cells. Inhibition of Bim expression by RNA interference transiently blocks luminal apoptosis and delays lumen formation. Oncogenes that induce acinar luminal filling, such as ErbB2 and v-Src, suppress expression of Bim through a pathway dependent on Erk-mitogen-activated protein kinase; however, HPV 16 E7, an oncogene that stimulates cell proliferation but not luminal filling, is unable to reduce Bim expression. Thus, Bim is a critical regulator of luminal apoptosis during mammary acinar morphogenesis in vitro and may be an important target of oncogenes that disrupt glandular epithelial architecture.

* Corresponding author. Mailing address: Harvard Medical School, Department of Cell Biology, 240 Longwood Ave., Boston, MA 02115. Phone: (617) 432-3974. Fax: (617) 432-3969. E-mail: Joan_Brugge{at}hms.harvard.edu.

{dagger} M.J.R. and K.R.M. contributed equally to this study.

{ddagger} Present address: Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102.

§ Present address: Cold Spring Harbor Laboratories, Cold Spring Harbor, NY 11274.

Molecular and Cellular Biology, June 2005, p. 4591-4601, Vol. 25, No. 11
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.11.4591-4601.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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