|
|
|
|
|
|
|
||||
| Home Help Feedback Subscriptions Archive Search Table of Contents | ||||
First published online 2 February 2005
doi: 10.1242/dev.01655
Departments of Cancer Biology, Cell and Developmental Biology, Medicine, and The Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6160, USA
Author for correspondence (e-mail:
chodosh{at}mail.med.upenn.edu)
Accepted 9 December 2004
Epidemiological findings suggest that the consequences of a given oncogenic stimulus vary depending upon the developmental state of the target tissue at the time of exposure. This is particularly evident in the mammary gland, where both age at exposure to a carcinogenic stimulus and the timing of a first full-term pregnancy can markedly alter the risk of developing breast cancer. Analogous to this, the biological consequences of activating oncogenes, such as MYC, can be influenced by cellular context both in terms of cell lineage and cellular environment. In light of this, we hypothesized that the consequences of aberrant MYC activation in the mammary gland might be determined by the developmental state of the gland at the time of MYC exposure. To test this hypothesis directly, we have used a doxycycline-inducible transgenic mouse model to overexpress MYC during different stages of mammary gland development. Using this model, we find that the ability of MYC to inhibit postpartum lactation is due entirely to its activation within a specific 72-hour window during mid-pregnancy; by contrast, MYC activation either prior to or following this 72-hour window has little or no effect on postpartum lactation. Surprisingly, we find that MYC does not block postpartum lactation by inhibiting mammary epithelial differentiation, but rather by promoting differentiation and precocious lactation during pregnancy, which in turn leads to premature involution of the gland. We further show that this developmental stage-specific ability of MYC to promote mammary epithelial differentiation is tightly linked to its ability to downregulate caveolin 1 and activate Stat5 in a developmental stage-specific manner. Our findings provide unique in vivo molecular evidence for developmental stage-specific effects of oncogene activation, as well as the first evidence linking MYC with activation of the Jak2-Stat5 signaling pathway.
Key words: Myc, Mammary, Differentiation, Stat5, Tgfß3, Caveolin 1, Mouse
Related articles in Development:
This article has been cited by other articles:
|
|
 |
|
  E. R. Andrechek, S. Mori, R. E. Rempel, J. T. Chang, and J. R. Nevins Patterns of cell signaling pathway activation that characterize mammary development Development, July 15, 2008; 135(14): 2403 - 2413. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Golipour, D. Myers, T. Seagroves, D. Murphy, G. I. Evan, D. J. Donoghue, R. A. Moorehead, and L. A. Porter The Spy1/RINGO Family Represents a Novel Mechanism Regulating Mammary Growth and Tumorigenesis Cancer Res., May 15, 2008; 68(10): 3591 - 3600. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Luo, Q. Li, J. O'Neal, F. Kreisel, M. M. Le Beau, and M. H. Tomasson c-Myc rapidly induces acute myeloid leukemia in mice without evidence of lymphoma-associated antiapoptotic mutations Blood, October 1, 2005; 106(7): 2452 - 2461. [Abstract] [Full Text] [PDF]
|
|
