A Functional Connection between pRB and Transforming Growth Factor β in Growth Inhibition and Mammary Gland Development

Abstract

Transforming growth factor β (TGF-β) is a crucial mediator of breast development, and loss of TGF-β-induced growth arrest is a hallmark of breast cancer. TGF-β has been shown to inhibit cyclin-dependent kinase (CDK) activity, which leads to the accumulation of hypophosphorylated pRB. However, unlike other components of TGF-β cytostatic signaling, pRB is thought to be dispensable for mammary development. Using gene-targeted mice carrying subtle missense changes in pRB (Rb1^ΔL and Rb1^NF), we have discovered that pRB plays a critical role in mammary gland development. In particular, Rb1 mutant female mice have hyperplastic mammary epithelium and defects in nursing due to insensitivity to TGF-β growth inhibition. In contrast with previous studies that highlighted the inhibition of cyclin/CDK activity by TGF-β signaling, our experiments revealed that active transcriptional repression of E2F target genes by pRB downstream of CDKs is also a key component of TGF-β cytostatic signaling. Taken together, our work demonstrates a unique functional connection between pRB and TGF-β in growth control and mammary gland development.

ACKNOWLEDGMENTS

We thank numerous colleagues for advice during the course of this research. The 3TP-lux plasmid was the kind gift of Shirin Bonni (University of Calgary). We are grateful for technical assistance from the CHRI histology and LHSC flow cytometry core facilities.

C.E.I., C.H.C., and S.M.F. have all been members of the CIHR-Strategic Training Program in Cancer Research and Technology Transfer. C.H.C. is the recipient of NSERC-CGS and OGS scholarships. S.M.F. acknowledges fellowship support from CBCF Ontario, as well as past support from OGSST. F.A.D. is a Research Scientist of the NCIC/CCS. This work was supported by operating grants from the NIH (CA058320) to J.Y.J.W. and from the Cancer Research Society and CIHR (MOP-64253) to F.A.D.

We declare that we have no competing financial interests.