Leptin--A Growth Factor in Normal and Malignant Breast Cells and for Normal Mammary Gland Development

Abstract Progesterone is a potent mitogen in the mammary gland. Based on studies using cells and animals engineered to express progesterone receptor (PR) isoforms A or B, PRA and PRB are believed to have different functions. Using an immunohistochemical approach with antibodies specific for PRA only or PRB only, we show that PRA and PRB expression in mammary epithelial cells is temporally and spatially separated during normal mammary gland development in the BALB/c mouse. In the virgin mammary gland when ductal development is active, the only PR protein isoform expressed was PRA. PRA levels were significantly lower during pregnancy, suggesting a minor role at this stage of development. PRB was abundantly expressed only during pregnancy, during alveologenesis. PRA and PRB colocalization occurred in only a small percentage of cells. During pregnancy there was extensive colocalization of PRB with 5-bromo-2′-deoxyuridine (BrdU) and cyclin D1; 95% of BrdU-positive cells and 83% of cyclin D1-positive cells expressed PRB. No colocalization of PRA with either BrdU or cyclin D1 was observed at pregnancy. In the virgin gland, PRA colocalization with BrdU or cyclin D1 was low; only 27% of BrdU-positive cells and 4% of cyclin D1-positive cells expressed PRA. The implication of these findings is that different actions of progesterone are mediated in PRB positive vs. PRA-positive cells in vivo. The spatial and temporal separation of PR isoform expression in mouse mammary gland provides a unique opportunity to determine the specific functions of PRA vs. PRB in vivo.

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Mammary Gland Specific Knockdown of the Physiological Surge in Cx26 during Lactation Retains Normal Mammary Gland Development and Function

PLoS ONE ◽

10.1371/journal.pone.0101546 ◽

2014 ◽

Vol 9 (7) ◽

pp. e101546 ◽

Cited By ~ 9

Author(s):

Michael K. G. Stewart ◽

Isabelle Plante ◽

John F. Bechberger ◽

Christian C. Naus ◽

Dale W. Laird

Keyword(s):

Mammary Gland ◽

Mammary Gland Development ◽

Normal Mammary Gland ◽

And Function ◽

Gland Development

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

Molecular and Cellular Biology ◽

10.1128/mcb.00473-09 ◽

2009 ◽

Vol 29 (16) ◽

pp. 4455-4466 ◽

Cited By ~ 15

Author(s):

Sarah M. Francis ◽

Jacqueline Bergsied ◽

Christian E. Isaac ◽

Courtney H. Coschi ◽

Alison L. Martens ◽

...

Keyword(s):

Mammary Gland ◽

Growth Factor ◽

Growth Inhibition ◽

Mammary Gland Development ◽

Transforming Growth Factor ◽

Critical Role ◽

Transforming Growth Factor Β ◽

Mammary Development ◽

Functional Connection ◽

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 Rb1NF ), 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.

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In vivo and in vitro evidence of basic fibroblast growth factor action in mouse mammary gland development

FEBS Letters ◽

10.1016/s0014-5793(98)01370-2 ◽

1998 ◽

Vol 439 (3) ◽

pp. 351-356 ◽

Cited By ~ 10

Author(s):

Sergio Lavandero ◽

Andrés Chappuzeau ◽

Mario Sapag-Hagar ◽

Takami Oka

Keyword(s):

Mammary Gland ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Basic Fibroblast Growth Factor ◽

Mammary Gland Development ◽

Mouse Mammary Gland ◽

Fibroblast Growth ◽

Gland Development

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Foxp3 heterozygosity does not overtly affect mammary gland development during puberty or the oestrous cycle in mice

Reproduction Fertility and Development ◽

10.1071/rd19378 ◽

2020 ◽

Vol 32 (8) ◽

pp. 774

Author(s):

Vahid Atashgaran ◽

Pallave Dasari ◽

Leigh J. Hodson ◽

Andreas Evdokiou ◽

Simon C. Barry ◽

...

Keyword(s):

Transcription Factor ◽

Mammary Gland ◽

Mammary Gland Development ◽

Cancer Susceptibility ◽

Branching Morphogenesis ◽

Genetic Mutation ◽

Oestrous Cycle ◽

Normal Mammary Gland ◽

Foxp3 Mrna ◽

Gland Development

Female mice heterozygous for a genetic mutation in transcription factor forkhead box p3 (Foxp3) spontaneously develop mammary cancers; however, the underlying mechanism is not well understood. We hypothesised that increased cancer susceptibility is associated with an underlying perturbation in mammary gland development. The role of Foxp3 in mammary ductal morphogenesis was investigated in heterozygous Foxp3Sf/+ and wildtype Foxp3+/+ mice during puberty and at specific stages of the oestrous cycle. No differences in mammary ductal branching morphogenesis, terminal end bud formation or ductal elongation were observed in pubertal Foxp3Sf/+ mice compared with Foxp3+/+ mice. During adulthood, all mice underwent normal regular oestrous cycles. No differences in epithelial branching morphology were detected in mammary glands from mice at the oestrus, metoestrus, dioestrus and pro-oestrus stages of the cycle. Furthermore, abundance of Foxp3 mRNA and protein in the mammary gland and lymph nodes was not altered in Foxp3Sf/+ mice compared with Foxp3+/+ mice. These studies suggest that Foxp3 heterozygosity does not overtly affect mammary gland development during puberty or the oestrous cycle. Further studies are required to dissect the underlying mechanisms of increased mammary cancer susceptibility in Foxp3Sf/+ heterozygous mice and the function of this transcription factor in normal mammary gland development.

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