Transforming growth factor-(beta)s and mammary gland involution; functional roles and implications for cancer progression - PubMed (original) (raw)
Transforming growth factor-(beta)s and mammary gland involution; functional roles and implications for cancer progression
Kathleen C Flanders et al. J Mammary Gland Biol Neoplasia. 2009 Jun.
Abstract
During rodent mammary gland involution there is a dramatic increase in the expression of the transforming growth factor-beta isoform, TGF-beta3. The TGF-betas are multifunctional cytokines which play important roles in wound healing and in carcinogenesis. The responses that are activated in the remodeling of the gland during involution have many similarities with the wound healing process and have been postulated to generate a mammary stroma that provides a microenvironment favoring tumor progression. In this review we will discuss the putative role of TGF-beta during involution, as well as its effects on the mammary microenvironment and possible implications for pregnancy-associated tumorigenesis.
Figures
Figure 1
Overview of the TGF-β/Smad signaling pathway. Latent TGF-β, bound to the ECM, undergoes an activation step (see text), releasing the TGF-β ligand which binds to the constitutively active Type II receptor at the cell surface. The Type I receptor is recruited into the complex where it is phosphorylated. The activated Type I receptor phosphorylates R-Smads (Smads 2 and 3) at the C-terminal serine residues and the R-Smads complex with the common mediator Smad4. This complex translocates to the nucleus where it regulates transcription of target genes and binds to a variety of transcription factors (TF).
Figure 2
Quantitation of TGF-β mRNA levels in the mammary gland from a virgin mouse (V), pregnant mouse at 15 d gestation (P), lactating mouse (L), and days 2, 4, 6, and 8 of involution.( ♦ TGF-β1, ■ TGF-β2, ▲, TGF-β3). Taken from Ref.(46) with kind permission of Springer Science+Business Media.
Figure 3
Involvement of TGF-β in different phases of rodent mammary gland involution. Milk stasis initiates involution as well as induces expression of TGF-β which in turn has effects on the processes indicated by arrows. A solid arrow indicates that a direct effect by TGF-β has been demonstrated in involution. A dashed arrow indicates a possible effect by TGF-β inferred from its biological activities in other systems. Double arrowheads indicate that these processes are also likely to result in production of additional TGF-β.
Figure 4
TGF-β3 mRNA expression in clinical breast cancer datasets. A. Inverse relationship between TGF-β3 mRNA expression and the histopathologic tumor grade. Data is shown for the study of Miller et al.(135), but a similar relationship was seen in 6 independent studies, using two different array platforms. B. Inverse relationship between TGF-β3 mRNA and metastasis at 5 years. Data is taken from the Van’t Veer study (105). Datamining of clinical breast cancer array datasets was done using Oncomine analysis tools (
). Boxes represent median and interquartile values, while whiskers represent the range. N represents the number of patients in each group.
References
- Monks J, Geske FJ, Lehman L, Fadok VA. Do inflammatory cells participate in mammary gland involution? J Mammary Gland Biol Neoplasia. 2002;7:163–176. - PubMed
- Strange R, Li F, Saurer S, Burkhardt A, Friis RR. Apoptotic cell death and tissue remodelling during mouse mammary gland involution. Development. 1992;115:49–58. - PubMed
- Schedin P. Pregnancy-associated breast cancer and metastasis. Nat Rev Cancer. 2006;6:281–291. - PubMed
- Schedin P, O'Brien J, Rudolph M, Stein T, Borges V. Microenvironment of the involuting mammary gland mediates mammary cancer progression. J Mammary Gland Biol Neoplasia. 2007;12:71–82. - PubMed
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