The Complex Role of Growth Hormone and Prolactin in Breast Cancer
Exploring the dual roles of GH and PRL in cancer dynamics.
Chen Chen, Jing Jiang, Tejeshwar C. Rao, Ying Liu, Tatiana T. Marquez Lago, Stuart J. Frank, André Leier
― 6 min read
Table of Contents
- Hormonal Connections to Cancer
- What Are These Receptors?
- The Signaling Process
- The Hormone Interaction Mystery
- The Effects of GH and PRL on Receptor Distribution
- Investigating Colocalization
- Altering Receptor Presence
- The Box1 Region: A Key Player
- Implications for Breast Cancer
- Future Directions
- Original Source
Growth Hormone (GH) and Prolactin (PRL) are important substances produced by the anterior pituitary gland in our brains. Think of them as the managers of different body processes. GH is all about growth and metabolism—it's the force behind how our bodies build and break down substances. On the other hand, PRL takes charge when it comes to breast development and feeding babies.
Not only do GH and PRL play crucial roles in body functions, but they also seem to have some involvement in cancer, particularly in Breast Cancer. There’s a lot of ongoing research about how these hormones and their Receptors can promote or even fight cancer.
Hormonal Connections to Cancer
Researchers have found that both GH receptors (GHR) and PRL receptors (PRLR) are often present in various types of cancer, including breast cancer (BC). In many cases, GHR shows up frequently, while PRLR is often overproduced. While these receptors have mainly been linked to supporting the growth of tumors, there are instances where PRL has acted more like a superhero by showing some anti-cancer effects.
Interestingly, a special type of antibody that targets PRLR didn’t show any anti-cancer effects in patients with advanced breast cancer that expressed PRLR. This raises questions about whether PRLR is as bad as previously thought or if it works differently depending on the context—like who else is hanging around (like other hormones).
What Are These Receptors?
Both GHR and PRLR are proteins that sit on the cell surface and are part of a larger family known as class I cytokine receptors. They are like bouncers outside a club, letting certain people in (hormones) to create changes inside the cell. Each of these receptors has specific parts that allow them to communicate with other proteins in the body.
GHR has a few versions, one of which is missing a section that connects with other proteins. PRLR also has different forms, including a long version and some shorter ones. These differences can change how they interact with hormones and respond to them.
Signaling Process
TheWhen GH binds to GHR or PRL attaches to PRLR, it causes changes inside the cells. However, neither receptor has the power to kick-start the action by itself—they need to partner with another protein called Janus kinase 2 (JAK2). JAK2 is like the sidekick that helps deliver the message inside the cell. This partnership helps activate other proteins that lead to various effects, such as growth or even changes in how genes are expressed.
The Hormone Interaction Mystery
It gets more interesting: there is evidence that GHR and PRLR can work together. Early studies showed that these two receptors could come together and change how they act after exposure to certain substances. In breast cancer cells, scientists found direct physical interactions between GHR and PRLR, which suggests that they may cooperate in ways previously unappreciated.
In recent studies, researchers used advanced imaging techniques to see how these two hormones interact on breast cancer cell surfaces. They discovered that the receptors form clusters, like groups of friends at a party. When the hormones are introduced, they see shifts in how many of these clusters exist, revealing a complex relationship affected by the presence of these hormones.
The Effects of GH and PRL on Receptor Distribution
During experiments, the effects of GH and PRL on the presence of GHR and PRLR on the cell surface were surprisingly clear. When treated with these hormones, the number of PRLR on the cell surface skyrocketed, while GHR started to disappear. This led scientists to wonder what role these changes play in cancer development.
When breast cancer cells were treated with GH or PRL, PRLR increased rapidly, while GHR decreased—even when PRL doesn't even bind to GHR. This curious phenomenon hints at deeper interactions between these hormones that could affect cancer progression.
Investigating Colocalization
Researchers looked closely at the spatial arrangement of these receptors, using techniques to see how close they were to each other on the cell surface. It turns out that GHR and PRLR are often found close together; they’re like two friends hanging out at a concert. However, when the hormones were introduced, the number of times they could be found together dropped significantly.
This indicates that the relationship between these two receptors can change based on hormonal signals, which may influence how cells behave, particularly in the context of cancer.
Altering Receptor Presence
A central finding in the research is that PRL can actively reduce the number of GHR on the cell surface, but this effect only happens when PRLR is also present. Scientists have created modified cells without PRLR to confirm this. In the absence of PRLR, PRL could not bring down GHR levels, which suggests that the presence of PRLR is crucial for this regulatory effect.
This observation could help explain how PRL might play a role in cancer. If PRL modulates the amount of GHR available on cell surfaces, it could influence how cells respond to growth signals.
The Box1 Region: A Key Player
A key piece of the puzzle is a specific area of the PRLR called the Box1 region. The studies indicate that this Box1 region is essential for the interaction between GHR and PRLR. When the Box1 area is altered or removed, the ability for PRL to reduce GHR levels is lost.
This reveals the importance of specific receptor domains in regulating how these hormones work together, and it suggests that understanding these details could lead to better treatments for hormone-related cancers.
Implications for Breast Cancer
This interplay between GH, PRL, and their receptors is particularly fascinating in the context of breast cancer. While some studies suggest that PRL can help fight cancer, others indicate it may promote it. The varying roles of PRL in different contexts warrant further investigation.
For instance, in some breast cancer cells, the presence of PRL seems to reduce the growth of tumors, while in others, it seems to have the opposite effect. This is an area ripe for exploration as scientists delve deeper into the complex world of hormone signaling and cancer.
Future Directions
Looking ahead, researchers hope to expand their investigations beyond the isolated cells used in current studies. They want to examine how these processes play out in other types of cells and the potential implications for therapies targeting these hormone interactions. There’s a lot of excitement about uncovering how GH and PRL might be manipulated to improve cancer treatments and potentially lead to new strategies for managing hormone-driven cancers like breast cancer.
In conclusion, GH and PRL might be well-known players in our bodies’ systems, but their roles are complex—especially concerning cancer. The interactions between their receptors create a dynamic landscape that could offer insights into new treatment possibilities. Scientists are on a quest to uncover the secrets of these hormones, and while there's a long road ahead, the journey is bound to yield some surprising discoveries.
So, who knew that these hormones were not just about growth and milk production but could also be players in the cancer game? Stay tuned, because science is always full of surprises!
Original Source
Title: A role for JAK2 in mediating cell surface GHR-PRLR interaction
Abstract: Growth hormone (GH) receptor (GHR) and (full-length) prolactin (PRL) receptor (PRLR) are transmembrane class I cytokine receptors that co-exist in various normal and cancerous cells. Both receptors respond to their associated ligands predominantly by activating the Janus Kinase 2 (JAK2)-signal transducer and activator of transcription (STAT) signaling pathways, and both are also known to initiate receptor-specific JAK2-independent signaling. Together with their cognate ligands, these receptors have been associated with pro-tumorigenic effects in various cancers, including breast cancer (BC). Human GH is known to bind GHR and PRLR, while PRL can only bind PRLR. A growing body of work suggests that GHR and PRLR can form heteromers in BC cells, modulating GH signal transduction. However, the dynamics of PRLR and GHR on the plasma membrane and how these could affect their respective signaling still need to be understood. To this end, we set out to unravel the spatiotemporal dynamics of GHR and PRLR on the surface of human T47D breast cancer cells and {gamma}2A-JAK2 cells. We applied direct stochastic optical reconstruction microscopy (dSTORM) and quantified the colocalization and availability of both receptors on the plasma membrane at the nanometer scale at different time points following treatment with GH and PRL. In cells co-expressing GHR and PRLR, we surprisingly observed that not only GH but also PRL treatment induces a significant loss of surface GHR. In cells lacking PRLR or expressing a mutant PRLR deficient in JAK2 binding, we observed that GH induces downregulation of cell surface membrane-bound GHR, but PRL no longer induces loss of surface GHR. Colocalizations of GHR and PRLR were confirmed by proximity ligation (PL) assay. Our results suggest that PRLR-GHR interaction, direct or indirect, is indispensable for PRL- but not GH- induced loss of surface GHR and for both GH-induced and PRL-induced increase of surface PRLR, with potential consequences for downstream signaling. Furthermore, our results suggest that JAK2 binding via the receptor intracellular domains Box1 element is crucial for the observed regulation of one class I cytokine receptors cell surface availability via ligand-induced activation of another class I cytokine receptor. Our findings shed new light on the reciprocal and collective role that PRLR and GHR play in regulating cell signaling.
Authors: Chen Chen, Jing Jiang, Tejeshwar C. Rao, Ying Liu, Tatiana T. Marquez Lago, Stuart J. Frank, André Leier
Last Update: 2024-12-19 00:00:00
Language: English
Source URL: https://www.biorxiv.org/content/10.1101/2023.09.01.555812
Source PDF: https://www.biorxiv.org/content/10.1101/2023.09.01.555812.full.pdf
Licence: https://creativecommons.org/licenses/by/4.0/
Changes: This summary was created with assistance from AI and may have inaccuracies. For accurate information, please refer to the original source documents linked here.
Thank you to biorxiv for use of its open access interoperability.