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Molecular and Cellular Biology, January 2007, p. 195-207, Vol. 27, No. 1
0270-7306/07/$08.00+0     doi:10.1128/MCB.01525-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Dormant Wnt-Initiated Mammary Cancer Can Participate in Reconstituting Functional Mammary Glands{triangledown}

Shelley A. Gestl,1,{dagger} Travis L. Leonard,1,{dagger} Jessica L. Biddle,1 Michael T. Debies,1 and Edward J. Gunther1,2*

Jake Gittlen Cancer Research Foundation,1 Department of Medicine, Pennsylvania State College of Medicine, Hershey, Pennsylvania 170332

Received 16 August 2006/ Returned for modification 13 September 2006/ Accepted 9 October 2006

The minimal residual disease foci that beget breast cancer relapse after a period of disease dormancy remain uncharacterized despite their enormous clinical importance. To model dormant breast cancer in vivo, we employed a transgenic mouse model in which Wnt1-initiated mammary cancer is doxycycline dependent. After regression of Wnt-dependent cancers, subclinical disease lesions were propagated in vivo using classical tissue recombination techniques. Surprisingly, outgrowths derived from dormant malignant tissue reconstituted morphologically normal ductal trees in wild-type mammary fat pads. Whereas hyperplasia-derived outgrowths remained benign, outgrowths derived from dormant malignancy underwent a morphological transition suggesting single-step transformation following reactivation of Wnt signaling and rapidly yielded invasive mammary tumors. Remarkably, outgrowths derived from dormant malignancy could be serially propagated in vivo and retained the potential to undergo lobuloalveolar differentiation in response to hormones of pregnancy. Matching somatic H-Ras mutations shared by antecedent tumors and descendant mammary ductal outgrowths confirmed their clonal relatedness. Thus, propagation of epithelium that possesses a latent malignant growth program reveals impressive regenerative and developmental potential, supporting the notion that dormant mammary cancers harbor transformed mammary progenitor cells. Our results define an experimental paradigm for elucidating biological properties of dormant malignancy.

* Corresponding author. Mailing address: Department of Medicine and Jake Gittlen Cancer Foundation, Pennsylvania State College of Medicine, Biomedical Research Building, H059, 500 University Drive, Hershey, PA 17033. Phone: (717) 531-7022. Fax: (717) 531-5634. E-mail: ejg12{at}psu.edu.

{triangledown} Published ahead of print on 23 October 2006.

{dagger} These authors contributed equally to this work.

Molecular and Cellular Biology, January 2007, p. 195-207, Vol. 27, No. 1
0270-7306/07/$08.00+0     doi:10.1128/MCB.01525-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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