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Cold Spring Harb Perspect Biol. 2012 February; 4(2): a013086.
PMCID: PMC3281567

On Hormone Action in the Mammary Gland

Abstract

The importance of systemic reproductive hormones in mammary gland development and breast cancer has been known for more than a century. In fact, the first targeted therapy for cancer was the development of tamoxifen, as an estrogen receptor (ER) antagonist. Based on studies performed primarily in a few breast cancer cell lines, the textbook concept of steroid hormone action at present is that on ligand binding, steroid receptors translocate into the nucleus and stimulate proliferation, and that this effect is mediated by specific coregulators. More recently, as nicely discussed by Brisken and O’Malley (2011), the concepts of specific receptor-positive sensor cells for systemic hormones, and paracrine mediators regulating the development and proliferation of proximal cells has been elegantly shown by the use of genetically engineered mice and chimeric transplantation experiments. One key question raised by these studies is, “How is the patterning of hormone receptor-positive sensor cells established during normal development?” As described by Visvader and Smith (2011), mammary stem cells lack the estrogen and progesterone receptors, and these receptors are first expressed at a still-undefined stage of the mammary cell hierarchy following the appearance of ductal and alveolar progenitors. So how is this process regulated appropriately to provide the correct temporal and spatial expression of the receptor-positive ductal and alveolar cells needed for normal ductal morphogenesis and alveolargenesis? Furthermore, what happens when this process is inappropriately regulated during early breast cancer progression when there may be a switch from paracrine to autocrine signaling mechanisms?

Until recently, it was not possible to study these processes in primary mammary epithelial cells, because when these cells are grown under conventional cell culture conditions they rapidly lose the expression of steroid receptors. However, some recent success in culturing both primary mouse and human mammary cells in embedded 3D Matrigel cultures have provided at least a surrogate system to help dissect some of these paracrine mechanisms (Novaro et al. 2003; Graham et al. 2009). Still, it has not been possible to precisely mimic the patterning of receptor-positive cells observed in vivo in these surrogate in vitro models. So how can we specifically target steroid receptor-positive sensor cells to perform gain- and loss-of-function experiments in vivo? Recent advances using genetically engineered mouse models (Jeong et al. 2010; Mukherjee et al. 2010) may provide the key. In these models, Lydon, Demayo, and colleagues (Jeong et al. 2010) have inserted the Cre recombinase into the progesterone receptor gene allowing specific gene deletion only in that subset of mammary epithelial cells. Because the majority of ER positive cells are also progesterone receptor positive, this should facilitate loss-of-function studies of paracrine mediators for both steroid hormone receptors. Conversely, using a clever bigenic system for doxycycline-inducible expression, these same investigators have expressed one of the identified paracrine mediators, RANKL, in the mammary epithelium of progesterone receptor knockout mice exclusively in ER positive cells. Thus, this gain-of-function approach should help define the critical paracrine mediators of progesterone action and perhaps even the role of specific coregulators in this subset of cells.

Downstream from the nuclear receptors, hormonal signaling is regulated by different chromatin contexts and differential recruitment of coactivators as well as corepressors (Brisken and O’Malley 2011). Numerous posttranslational modifications also play key roles in modulating the effects of coregulators, but these have been studied primarily in the HeLa, and to a lesser extent in MCF7, cell lines. Thus, we still know very little about these coregulators and their modifications in normal mammary epithelial cells. Because cell context and architecture are critical, studies, therefore, should be performed in primary mammary epithelial cells to provide a better understanding of how these coregulators and their posttranslational modifications affect normal mammary gland development. No doubt, coregulators may differentially influence hormone receptor-positive cells as compared to the receptor-negative adjacent cells, because most coregulators can also affect cells lacking steroid hormone receptors. Clearly, we are only at the tip of the iceberg when it comes to understanding the precise molecular mechanisms of hormone action in the normal mammary gland, and this will be critical for identifying alterations which occur during breast cancer progression.

Footnotes

Editors: Mina J. Bissell, Kornelia Polyak, and Jeffrey M. Rosen

Additional Perspectives on The Mammary Gland as an Experimental Model available at www.cshperspectives.org

REFERENCES

*Reference is also in this collection.

* Brisken C, O'Malley B 2011. Hormone action in the mammary gland. Cold Spring Harb Perspect Biol. doi: 10.1101/cshperspect.a003178. [PMC free article] [PubMed] [Cross Ref]
Graham JD, Mote PA, Salagame U, Balleine RL, Huschtscha LI, Clarke CL 2009. Hormone-responsive model of primary human breast epithelium. J Mammary Gland Biol Neoplasia 14: 367–379. [PubMed]
Jeong JW, Kwak I, Lee KY, Kim TH, Large MJ, Stewart CL, Kaestner KH, Lydon JP, Demayo FJ 2010. Foxa2 is essential for mouse endometrial gland development and fertility. Biol Reprod 83: 396–403. [PMC free article] [PubMed]
Mukherjee A, Soyal SM, Li J, Ying Y, He B, Demayo FJ, Lydon JP 2010. Targeting RANKL to a specific subset of murine mammary epithelial cells induces ordered branching morphogenesis and alveologenesis in the absence of progesterone receptor expression. FASEB J 24: 4408–4419. [PubMed]
Novaro V, Roskelley CD, Bissell MJ 2003. Collagen-IV and laminin-1 regulate estrogen receptor α expression and function in mouse mammary epithelial cells. J Cell Sci 116: 2975–2986. [PMC free article] [PubMed]
* Visvader JE, Smith GH 2011. Murine mammary epithelial stem cells: Discovery, function, and current status. Cold Spring Harb Perspect Biol. doi: 10.1011/cshperspect.a004879. [PMC free article] [PubMed] [Cross Ref]

Articles from Cold Spring Harbor Perspectives in Biology are provided here courtesy of Cold Spring Harbor Laboratory Press