Slow-Growing ER+ Breast Cancer Cells and How Rac-1 and The IGF Axis Supports Relapse
A new ER+ breast cancer paper shows that some cells survive therapy by going slow, entering a senescent‑like state and wiring in a Rac1–IGF‑axis survival circuit that supports late relapse.
In this section
Part One — the paper
Part Two — our response
How our key natural compounds line up with the IGF1R/IR escape axis
3. Berberine — pressing on the same survival tracks downstream
Part 1 — what this ER+ breast cancer paper shows
The paper at a glance
Endocrine therapy reprogramming of breast cancer facilitates metastatic escape via upregulation of P-Rex1/Rac1 signalling
The big question the paper asks
For many people with ER+ breast cancer, endocrine therapy (like tamoxifen or aromatase inhibitors) works well for years. But a significant number later develop metastatic disease, sometimes a decade or more after the original diagnosis and treatment.
This paper asks:
What kind of cells manage to survive endocrine therapy?
How do those cells behave?
Is there a particular signalling pathway they use to “escape” and form metastases?
The authors build models to mimic slow‑growing, endocrine‑tolerant ER+ cells and then look closely at what makes them special.
Key idea 1 – “Slow but dangerous” cells
The researchers find a population of cells that:
Grow slowly (low proliferation, low Ki‑67 compared with other cancer cells)
Still manage to form metastases in mice
Have features that look “senescent‑like”:
Enlarged, sometimes multi‑nucleated cells
Increased senescence‑associated β‑galactosidase staining
Collagen‑rich, fibrous tissue around them
These are not fast, aggressive, highly dividing cells. They are more like “parked” cells that are still alive, stress‑adapted, and able to travel and seed new sites.
What is “senescent‑like”?
“Senescence” usually means a permanent growth arrest: cells stop dividing but stay metabolically active and often secrete inflammatory and growth factors (the SASP).
In this paper, the cells are described as “senescent‑like” because they show many senescence markers (shape, β‑gal, reduced HMGB2, altered mitochondrial pathways), but they still have enough functional capacity to survive, move, and eventually fuel recurrence.
Think: not dead, not really normal, not highly proliferative – but stubborn survivors.
Key idea 2 – A Rac1 escape pathway is switched on
When the authors look at gene expression and signalling networks in these slow‑cycling, endocrine‑tolerant cells, one pathway stands out:
A P‑Rex1–Rac1–PAK2 signalling hub is strongly up-regulated.
This hub connects to IGF1R/insulin receptor survival signalling.
In simpler terms:
P‑Rex1 is a molecule that switches on Rac1 (a small GTPase that helps cells change shape, move, and survive).
Rac1, together with PAK2 and IGF1R/IR signalling, helps these cells:
Resist treatment stress
Migrate and invade
Persist long‑term despite slow growth
The paper shows that Rac1 activity is higher in endocrine‑tolerant models and that Rac1 signalling is particularly enriched in ER+ disease, including late recurrences and metastases.
Where does Rac1 sit compared to SASP and autophagy?
In this paper, Rac1 is not presented as the “master controller” of SASP or autophagy.
Instead, it acts as a senescence‑associated escape pathway: a wiring that sits on top of a senescent‑like state and gives cells motility and survival capacity.
The focus is on Rac1’s role in:
Cell movement and invasion
Survival signalling (especially via IGF1R/IR)
So, Rac1 is more like the “get away car” for senescent‑like cells rather than the core engine of SASP or autophagy here.
Key idea 3 – Targeting Rac1 can weaken these escapee cells
The authors test Rac1 pathway inhibition using small‑molecule inhibitors (pharmaceutical agents):
Rac1 inhibitors reduce survival and motility of endocrine‑resistant cells in lab models.
In mouse models, blocking Rac1 signalling decreases tumour burden when combined with endocrine therapy.
This supports the idea that Rac1 is not just a passenger; it is functionally important for the survival and spread of these slow‑growing, resistant cells.
This is crucial conceptually: it suggests that late recurrence is not just about “dormant cells waking up” but also about a senescent‑like, Rac1‑driven survival and migration program that can be therapeutically targeted.
Why this matters to patients
For patients with ER+ breast cancer, this paper helps explain:
Why late recurrences often show low proliferation but are still lethal.
Why simply focusing on cell division markers (like Ki‑67) may miss the “problem population”.
How a specific signalling axis (P‑Rex1–Rac1–PAK2–IGF1R) can support long‑term survival and metastasis of therapy‑experienced cells.
The important message is:
"Some ER+ cancer cells survive endocrine therapy by entering a slow‑growing, senescent‑like state supported by a Rac1‑based survival and migration signalling. This makes them harder to detect, but potentially targetable if we focus on survival, motility, and microenvironment rather than proliferation alone."
Questions and answers
Q. “I’ve heard of ketorolac. Why can’t we just use it to fix the Rac1 problem?”
A. Here’s the simple version of why it’s not that straightforward:
The ketorolac you get for pain is a 50:50 mix
Hospital ketorolac contains two mirror‑image forms: S‑ketorolac and R‑ketorolac.
The S‑form is what gives you pain relief and also most of the classic NSAID risks (stomach, kidney, bleeding).
The R‑form is the one the cancer paper is interested in, because it can block Rac1‑type signalling in lab models.
Doses are chosen for pain, not for Rac1
All current dosing guidelines were designed to get good pain control from the S‑form.
Nobody has worked out a safe, proven “Rac1‑targeting dose schedule” in people with breast cancer.
So if you used standard ketorolac hoping to hit Rac1, you’d mostly be following pain‑medicine rules, not Rac1‑inhibition science.
Extra risk, unclear benefit
To get enough R‑ketorolac exposure for a potential Rac1 effect, you might have to use ketorolac more or longer than is safe from a pain‑medicine perspective.
You’d be taking on NSAID‑type risks (gut, kidney, bleeding, immune) for a Rac1 benefit that hasn’t yet been proven in real‑world ER+ survivors.
The research used R‑ketorolac as a lab tool, not as a clinic protocol
In the paper, R‑ketorolac is used to show “if we block Rac1, these resistant cells become more vulnerable”.
That’s a proof‑of‑concept, not yet a ready‑to‑use treatment recipe for patients.
Ketorolac (the pain drug) does contain the R‑form that can block Rac1 in lab experiments, but it’s not designed or sold in a singled-out form for use in people with cancer. Right now, it’s a research clue that Rac1 is a valid target, not a self‑serve solution we can safely apply.
References for Part 1
References for Part 1
“Endocrine therapy reprogramming of breast cancer facilitates metastatic escape via upregulation of P‑Rex1–Rac1 signalling”, Nature Communications 2026.
URL: https://www.nature.com/articles/s41467-026-70683-x“The P‑Rex1/Rac signalling pathway as a point of convergence for HER/ErbB receptor and G protein‑coupled receptor signalling in breast cancer cells”, Breast Cancer Research 2016.
URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC5997144/“Rac1 GTPase regulates cell genomic stability and senescence”, Cancer Research 2006.
URL: https://pubmed.ncbi.nlm.nih.gov/17032649/“IGF1R signaling drives antiestrogen resistance through PAK2 in breast cancer”, Oncogene 2018.
URL: https://pubmed.ncbi.nlm.nih.gov/29353882/“Pharmacological inhibition of Rac1-PAK1 axis restores tamoxifen sensitivity in resistant breast cancer cells”, Molecular Cancer Therapeutics 2017.
URL: https://pubmed.ncbi.nlm.nih.gov/27939839/
Part 2 — how our key natural compounds line up with the IGF1R/IR escape axis
Taking action
The new ER+ paper shows that slow‑cycling, senescent‑like, endocrine‑tolerant cells lean heavily on two things:
A P‑Rex1–Rac1–PAK2 signalling node
IGF1R/IR signalling as a key part of their survival wiring
For this section, we zoom in on our “go‑to” natural compounds that have evidence for:
Modulating IGF1R or insulin receptor (IR) activity, and/or
Hitting downstream survival pathways that IGF1R/IR use (PI3K/Akt/mTOR, anti‑apoptotic signalling)
In other words, these are compounds that appear to press on the same survival path that Rac1‑driven, endocrine‑tolerant cells rely on.
1. EGCG — closest to the IGF1/IGF1R/IR axis
EGCG (from green tea) has two lines of evidence that make it relevant to the IGF1/IGF1R/IR escape axis:
In breast cancer, EGCG clearly acts on the same survival environment that IGF1R feeds into. In ERα‑positive MCF‑7 cells, EGCG inhibits growth and reduces protein levels of HIF‑1α and VEGF, and other work shows it can reduce invasion and Akt activation in endocrine‑resistant MCF‑7‑derived cells. These are the same hypoxia and growth‑factor pathways that cooperate with IGF1R signalling in hormone‑positive disease.
In other cancer models (e.g. colon and hepatocellular carcinoma), EGCG has directly modulated the IGF axis by lowering IGF‑1 and IGF‑2, increasing IGFBP‑3, and reducing IGF1R phosphorylation, thereby weakening IGF‑driven survival signalling.
How that fits the ER+ Rac1/IGF1R story
In the new ER+ paper, the slow‑growing, Rac1‑high cells depend on IGF1R/IR signalling to stay alive. EGCG aligns with that picture by:
Acting directly on IGF/IGF1R signalling in non‑breast cancer models.
Modulating key downstream survival programmes (HIF‑1α, VEGF, Akt) and being formally tested against IGF‑1/IGFBP‑3 in breast‑risk trials.
Liposomal EGCG is the closest fit to the IGF1/IGF1R/IR node that the ER+ Rac1 paper highlights, and sits naturally next to endocrine therapy as part of an “IGF‑axis pressure” strategy.
References for this section
“EGCG decreases the expression of HIF‑1α and VEGF and inhibits the growth of MCF‑7 breast cancer cells.”
URL: https://pubmed.ncbi.nlm.nih.gov/24965403/“EGFR inhibition by (-)-epigallocatechin-3-gallate and IIF treatments reduces breast cancer cell invasion.”
URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC5434892/“EGCG inhibits activation of the insulin-like growth factor-1 receptor in human hepatocellular carcinoma cells.”
URL: https://pubmed.ncbi.nlm.nih.gov/18164805/“EGCG inhibits activation of the insulin-like growth factor-1 receptor in human colon cancer cells.”
URL: https://www.sciencedirect.com/science/article/abs/pii/S0006291X05014300
Why Liposomal EGCG is a good fit for this “escape pathway”
EGCG as already discussed has research showing it can dial down IGF1R/insulin‑receptor signalling in cancer cells – the same survival axis that the new ER+ paper highlights in Rac1‑driven, endocrine‑tolerant cells.
When EGCG is delivered in a liposomal form, there are two extra advantages that make it a particularly good fit for a “post‑treatment dormancy” context:
Better delivery into macrophages:
Liposomes are readily taken up by phagocytic cells like macrophages. Studies using nano‑encapsulated EGCG show much higher accumulation of EGCG inside macrophages, with stronger anti‑inflammatory and chemokine‑lowering effects than the same dose of free EGCG.Shaping tumour‑associated macrophages (TAMs):
In murine breast cancer models, EGCG treatment has been linked to reduced tumour‑associated macrophage infiltration and a shift away from a tumour‑promoting M2‑like profile, with lower IL‑6 and TGF‑β and relatively higher TNF‑α. This is important, because M2‑skewed macrophages in the tumour microenvironment are known to support cancer cell survival, immune evasion and dormancy niches.
A liposomal EGCG formulation not only targets cancer‑cell survival signalling (including IGF1R/IR), it is also well‑positioned to get into macrophages and help push the immune microenvironment away from a pro‑tumour, M2‑dominated state that favours long‑term post‑treatment dormancy.
Members experience:
A member targeting M2 and IGF1R/IR axis reports using a very small cordless electric milk frother/ whisk and tiny 50ml measuring cup and pouring in 10ml of Liposence adding 5ml water and the contents of 2 x 80% extract capsules each being 400mg each. Whisking well then dividing the contents of the cup by three daily doses. More on Liposence and liposomes here.
2. Curcumin — blocking IGF1R-driven survival signals
What the research shows
Curcumin can reduce IGF1R expression (mRNA and protein) in certain cancer models.
It can block IGF‑1‑induced activation of the IGF1R β‑subunit and its key downstream targets such as Akt (PKB) and GSK‑3β.
IGF1R is one of the main survival arms for the senescent‑like, endocrine‑tolerant cells in the new ER+ study. Curcumin’s ability to:
Lower IGF1R levels, and
Block IGF‑1‑triggered signalling through Akt and GSK‑3β
Curcumin is best described as a mTOR/BCL‑2‑modulating compound that also leans hard on the IGF1R survival pathway. Paired with EGCG, it gives us a natural “double hit” on IGF1R‑centred signalling.
“Curcumin inhibits growth and triggers apoptosis in human cancer cells by down-regulating IGF-1R.”
URL: https://journals.sagepub.com/doi/10.1177/03000605231220807“Insulin-like growth-factor-1-induced PKB signaling and Egr-1 expression in vascular smooth muscle cells: inhibition by curcumin.”
URL: https://pubmed.ncbi.nlm.nih.gov/23537438/
It's well worth bookmarking and reading the Curcumin in Oncology section of this site.
3. Berberine — pressing on the same survival tracks downstream
Berberine doesn’t often get labelled as an “IGF1R inhibitor”, but it keeps showing up on the same survival and growth pathways that sit just downstream of IGF1R/IR.
In breast cancer models, berberine reduces growth and metastasis by dampening PI3K/Akt/mTOR signalling and HIF‑1α‑driven programmes, both of which are key escape routes for hormone‑positive disease.
Recent work in breast cancer also shows that berberine suppresses proliferation, invasion and migration and induces apoptosis partly by changing the stability and translation of growth‑factor mRNAs (for example FGF7), which plugs directly into growth‑factor and IGF‑related signalling loops.
"Berberine helps switch off survival and growth pathways that sit downstream of IGF1R/IR (PI3K/Akt/mTOR, HIF‑1α and growth‑factor feedback loops), even if it isn’t branded in the literature as a classic “IGF1R blocker”.
EGCG and curcumin are your most direct IGF1R/IR go‑to compounds, and berberine still belongs firmly in the same “survival axis pressure” story.
“Berberine inhibits the progression of breast cancer by regulating METTL3-mediated m6A modification of FGF7 mRNA.”
URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC11168909/“Berberine and its anticancer effects: a review.”
URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC6996556/
And for an overview of why PI3K/Akt/mTOR is such a key resistance pathway in hormone‑positive breast cancer, see ‘Targeting the PI3K/AKT/mTOR pathway in hormone-positive breast cancer https://pmc.ncbi.nlm.nih.gov/articles/PMC7572750/
It's well worth bookmarking and reading the Berberine in Oncology section of this site.
In ER+ breast cancer cells, IGF‑1 activates the type I IGF receptor and then the PI3K/Akt pathway, helping cancer cells resist death and promoting metastatic behaviour. Blocking this IGF‑1R–PI3K/Akt axis restores vulnerability to cell death.
In a nutshell
This new ER+ paper tells us that some therapy‑experienced cells survive by going slow, switching into a senescent‑like state, and leaning on a Rac1–IGF1R/IR survival pathway rather than on fast proliferation. In our natural‑compound world, we don’t have a direct Rac1 drug, but we do have a small group of well‑studied tools that press on the same survival wiring. Liposomal EGCG and curcumin sit closest to the actual IGF1R/IR node, helping to turn down the growth‑factor signals these escapee cells depend on, while berberine pushes further downstream on shared tracks like PI3K/Akt/mTOR and HIF‑1α. Together, they give us a coherent, research‑aligned way to think about supporting standard care: not by replacing endocrine therapy, but by adding pressure on the very signalling routes this paper has highlighted as critical for late ER+ escape and dormancy.
Member Questions and Answers
Q. If I’m already using liposomal EGCG, Curcumin and Berberine does that mean I don’t need a senolytic “pulse” anymore?
A. No – they do different jobs, and both sides matter.
EGCG, Curcumin and Berberine are best thought of as daily “survival‑pathway pressure” tools. They lean on the same IGF1R/IR and downstream signalling tracks that the new ER+ paper highlights, making it harder for slow‑cycling, therapy‑experienced cells to stay comfortable and well‑fed.
The senolytic pulse has a different role. Senescent and therapy‑damaged cells often protect themselves by over‑expressing BCL‑2‑family survival proteins (BCL‑2, BCL‑xL, BCL‑W).
Short pulsed senolytic protocols are designed to hit those survival shields directly and make it easier for the body to clear out these stubborn, “not dead but not normal” cells.
So in this framework:
EGCG + curcumin + berberine = ongoing pressure on the escape pathways (IGF1R/IR, PI3K/Akt/mTOR, related survival signalling).
Pulsed senolytic pulse = monthly 3 day periodic “clean‑up” aimed at senescent cells that are hiding behind BCL‑2‑style defences.
They are complementary, not substitutes.
Senolytic Pulse Protocol
If the next practical question is how to structure that senolytic pulse, see Senolytic Pulse Protocol.
That page takes the monthly “clean-up” idea one step further.
It lays out a patient-facing pulse framework built around fisetin and quercetin.
It also explains why intermittent pulse dosing fits the current human evidence better than continuous daily use.
Senolytics Q&A References
Senolytics: charting a new course or enhancing existing anti-tumor therapies https://pmc.ncbi.nlm.nih.gov/articles/PMC11996976/
Therapy-Induced Senescence: Opportunities to Improve Anticancer Therapy https://academic.oup.com/jnci/article/113/10/1285/6207975
New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors https://www.aging-us.com/article/101202/text
A phase II randomized placebo-controlled study of fisetin to improve physical function in breast cancer survivors https://pubmed.ncbi.nlm.nih.gov/41835341/