How Hormones Rewire Breast Cancer
In the microscopic world of our cells, a complex dialogue between hormones is reshaping our understanding of breast cancer.
When we think about breast cancer, we often hear about estrogen as a key player. But cutting-edge research is revealing a more complex story, where multiple hormones interact in a delicate dance, sometimes collaborating, sometimes competing. At the heart of this story is a little-known enzyme called prolidase that's turning out to be a master regulator of cellular communication. This hidden conversation between prolactin, estrogen, and prolidase isn't just academic—it may hold the key to more effective, less toxic treatments for one of the world's most common cancers.
of breast cancers are estrogen-receptor-positive
of patients don't respond to initial anti-estrogen treatments
Year prolidase's dual function was discovered
For decades, estrogen has taken center stage in our understanding of hormone-responsive breast cancer. Approximately 70% of breast cancers are estrogen-receptor-positive, making anti-estrogen therapies like tamoxifen cornerstone treatments. But about 30% of patients don't respond to these treatments initially, and many others develop resistance over time1 .
Enter prolactin, a hormone best known for its role in milk production but now recognized as a significant contributor to breast cancer. Meanwhile, prolidase—previously thought to simply recycle protein building blocks—has been revealed as a surprising double agent with crucial roles in cellular signaling. When these players interact in MCF-7 cells (a common model for estrogen-responsive breast cancer), they create a complex web of communication that can either suppress or promote cancer growth, depending on the context.
The interaction between prolactin, estrogen, and prolidase creates a complex signaling network that influences cancer cell behavior and treatment response.
Prolidase, known scientifically as PEPD, is no ordinary enzyme. For decades, researchers viewed it as a simple housekeeping protein responsible for cleaving dipeptides containing proline or hydroxyproline at their C-terminal ends—essentially recycling protein fragments. This function is particularly important for collagen metabolism, since proline and hydroxyproline make up over 20% of collagen, the body's most abundant protein4 .
But in 2020, a paradigm-shifting discovery revealed that prolidase wears another hat: it functions as a ligand for epidermal growth factor receptors (EGFR and HER2)2 . These receptors are like cellular antennas, detecting growth signals and telling cells when to divide. When prolidase binds to them, it activates multiple signaling pathways that influence cell behavior, including the PI3K/Akt/mTOR, Ras/Raf/ERK, and JAK/STAT3 pathways2 .
Cleaves dipeptides with proline or hydroxyproline at C-terminal ends, recycling protein fragments.
Acts as ligand for EGFR and HER2 receptors, activating multiple cellular pathways.
What makes this dual role particularly fascinating is that prolidase doesn't need its enzymatic activity to function as a signaling molecule. Even enzymatically "dead" prolidase can still activate these important pathways2 . This means our cells have evolved a single protein that can perform two completely independent jobs—a efficient multitasker in the complex world of cellular regulation.
To understand how these pieces fit together, let's examine a crucial 2024 study that investigated how prolactin pretreatment affects tamoxifen sensitivity in MCF-7 breast cancer cells3 .
The research team designed a straightforward but elegant experiment:
They maintained MCF-7 cells (a standard estrogen receptor-positive breast cancer cell line) in specialized laboratory conditions.
One group of cells received 250 ng/ml of recombinant human prolactin for either 72 hours or 21 days. Another group served as an untreated control.
Both the prolactin-pretreated and untreated cells were then exposed to varying concentrations of tamoxifen (0-100 μM) for 72 hours.
The researchers used Sulforhodamine B (SRB) and MTT assays—standard laboratory methods for measuring cell growth and viability—to determine how many cells survived each treatment condition.
| Phase | Duration | Treatment Groups | Key Measurements |
|---|---|---|---|
| Pretreatment | 72 hours or 21 days | Prolactin (250 ng/ml) vs. No treatment | Cell differentiation markers |
| Tamoxifen Exposure | 72 hours | 0-100 μM tamoxifen | Cell viability, proliferation |
| Analysis | Post-treatment | Comparison between groups | SRB and MTT assay results |
The findings were striking. Cells that received prolactin pretreatment showed significantly enhanced sensitivity to tamoxifen compared to untreated cells3 . This meant that lower doses of tamoxifen were needed to achieve the same cancer-killing effect in prolactin-treated cells.
Visual representation of the enhanced sensitivity to tamoxifen after prolactin pretreatment
The researchers proposed a mechanism: prolactin was pushing the cancer cells toward a more differentiated, less aggressive state. In simple terms, the cells were becoming more "mature" and less like stem cells—a process that made them vulnerable to anti-estrogen therapy. This aligned with their additional finding that co-expression of prolactin receptors and estrogen receptors in human patients correlated with better differentiation and improved outcomes3 .
| Parameter | Prolactin-Pretreated Cells | Untreated Control Cells |
|---|---|---|
| Tamoxifen Sensitivity | Significantly Enhanced | Standard response |
| Proposed Cellular State | More differentiated, less aggressive | Less differentiated |
| Clinical Correlation | Better patient outcomes | Standard outcomes |
| Potential Treatment Implications | Lower effective drug doses possible | Standard doses required |
This experiment becomes even more meaningful when viewed alongside earlier research on how prolactin and estrogen interact. Back in 2005, scientists discovered that these two hormones can cooperatively enhance the activity of AP-17 —a transcription factor complex that regulates processes essential for both normal growth and cancer development.
Prolactin and estrogen bind to their respective receptors on the cell surface or in the cytoplasm.
Intracellular signaling cascades are activated, including JAK/STAT, MAPK, and PI3K pathways.
AP-1 and other transcription factors are activated, regulating gene expression.
Cells undergo changes in proliferation, differentiation, or apoptosis based on the signals received.
What's remarkable is the timing of their effects. Prolactin rapidly activates AP-1 within hours, while estrogen's effects are more delayed but sustained. When both hormones are present, they create a synergistic activation of signaling pathways that leads to increased phosphorylation of ERK1/2 and c-Fos, ultimately enhancing AP-1 activity beyond what either hormone could achieve alone7 .
This collaboration matters because AP-1 regulates genes involved in proliferation, survival, and invasion—all processes that go haywire in cancer. The prolonged presence of both hormones creates a sustained activation that may contribute to neoplastic progression.
Studying these complex interactions requires specialized tools. Here are some of the key reagents that enable this critical research:
| Reagent | Function in Research | Specific Example |
|---|---|---|
| MCF-7 Cell Line | Model system for estrogen receptor-positive breast cancer | Human breast adenocarcinoma cells with estrogen, androgen, progesterone receptors1 |
| Recombinant Human Prolactin (rhPRL) | Investigate prolactin-specific effects | 250 ng/ml for cell stimulation3 |
| Tamoxifen Citrate | Selective estrogen receptor modulator for treatment studies | 0-100 μM dose range for sensitivity assays3 |
| AP-1 Reporter Plasmid | Measure AP-1 transcription factor activity | 4XAP-1-luc construct with four AP-1 tandem repeats7 |
| Sulforhodamine B (SRB) Assay | Measure cell viability and proliferation | Protein-binding dye for spectrophotometric reading3 |
The discovery that prolactin can drive breast cancer cells toward a more differentiated, treatment-responsive state opens exciting possibilities for clinical innovation. Rather than simply blocking hormones, we might eventually guide cancer cells into less dangerous states—essentially convincing them to mature rather than multiply uncontrollably.
Using hormones like prolactin as pre-treatment before conventional therapies to enhance their effectiveness3
Lower doses of toxic drugs like tamoxifen could be used if cells are first sensitized with prolactin
Strategically timing prolactin administration with anti-estrogen therapies to maximize effectiveness
How can we precisely control differentiation signals without encouraging growth? Would this approach work in actual tumors, not just cell lines? These are active areas of investigation that will keep scientists busy for years to come.
The complex cross-talk between prolactin, estrogen, and prolidase in MCF-7 cells reveals a fundamental truth about biology: nothing in our cells operates in isolation. The future of breast cancer treatment may lie not in simply blocking single hormones, but in understanding and influencing these complex cellular conversations to guide cells toward less dangerous behaviors.
As research continues to unravel these intricate relationships, we move closer to a day when breast cancer treatment is not just about poisoning rapidly dividing cells, but about intelligently reprogramming cellular decision-making—a approach that could be more effective and less toxic for patients worldwide.
References will be listed here in the final version.