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Published online 22 October 2001. doi:10.1083/jcb.200011001
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© The Rockefeller University Press, 0021-9525/2001/10/471 $5.00
The Journal of Cell Biology, Volume 155, Number 3, October 29, 2001 471-486

Article

 Suppression of p53 function in normal human mammary epithelial cells increases sensitivity to extracellular matrix–induced apoptosis

Victoria L. Seewaldt1, Krzysztof Mrózek2, Randy Sigle3, Eric C. Dietze1, Kevin Heine4, David M. Hockenbery4, Katherine B. Hobbs1 and L. Elizabeth Caldwell5

1 Division of Medical Oncology, Duke University, Durham, NC 27710
2 Division of Hematology and Oncology and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210
3 Division of Basic Science, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
4 Division of Clinical Research and Molecular Medicine, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
5 Program in Electron Microscopy, Fred Hutchinson Cancer Research Center, Seattle, WA 98109

Address correspondence to Victoria L. Seewaldt, Box 2628, Duke University Medical Center, Durham, NC 27710. Tel.: (919) 668-2455. Fax: (919) 668-2458. E-mail: seewa001{at}mc.duke.edu

Little is known about the fate of normal human mammary epithelial cells (HMECs) that lose p53 function in the context of extracellular matrix (ECM)–derived growth and polarity signals. Retrovirally mediated expression of human papillomavirus type 16 (HPV-16) E6 and antisense oligodeoxynucleotides (ODNs) were used to suppress p53 function in HMECs as a model of early breast cancer. p53+ HMEC vector controls grew exponentially in reconstituted ECM (rECM) until day 6 and then underwent growth arrest on day 7. Ultrastructural examination of day 7 vector controls revealed acinus-like structures characteristic of normal mammary epithelium. In contrast, early passage p53- HMEC cells proliferated in rECM until day 6 but then underwent apoptosis on day 7. p53- HMEC-E6 passaged in non-rECM culture rapidly (8–10 passages), lost sensitivity to both rECM-induced growth arrest and polarity, and also developed resistance to rECM-induced apoptosis. Resistance was associated with altered expression of {alpha}3-integrin. Treatment of early passage p53- HMEC-E6 cells with either {alpha}3- or ß1-integrin function-blocking antibodies inhibited rECM-mediated growth arrest and induction of apoptosis. Our results indicate that suppression of p53 expression in HMECs by HPV-16 E6 and ODNs may sensitize cells to rECM-induced apoptosis and suggest a role for the {alpha}3/ß1-heterodimer in mediating apoptosis in HMECs grown in contact with rECM.

Key Words: extracellular matrix; mammary epithelial cells; apoptosis; p53; {alpha}3/ß1-integrin


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