Could tamoxifen lead a new strategy to fight cancer?
 

Armando del Río Hernández, PhD。

Cellular and Molecular Biomechanics Laboratory

Department of Bioengineering, Imperial College, London

www.biomechanicalregulation-lab.org

E: a.del-rio-hernandez@imperial.ac.uk

T: +44 207 594 5187

 

For many years tamoxifen has been known as an estrogen analogue used to treat breast cancer based on its effect through the classical estrogen receptors alpha and beta (ERa and ERb), expressed mostly in breast epithelial cells.

In a series of publications1-3 (links below) we present a new role of tamoxifen as a regulator of the tumor microenvironment and the cancer associated myofibroblast-like cells. This mechanism is ERa and ERb independent and instead involves the activation of G coupled-protein estrogen receptor (GPER) and the RhoA/myosin/YAP axis3.

We also report that tamoxifen negatively regulates Hypoxia Inducible Factor -1alpha (HIF-1A) in stromal and cancer cells through a hypoxia independent mechanism2. This opens the possibility to reprogram the mechanosensory machinery in these cells to modulate their proliferation under hypoxic conditions by targeting HIF-1A.

The concept of tamoxifen as a regulator of cell mechanics via GPER is new in medicine and biology, and the ubiquitous expression of the GPER receptor offers the opportunity to use tamoxifen to redirect the singular focus on the cancer cells to the greater tumour microenvironment and other cell types in different diseases. Given that GPER belongs to the GPCR family and holds the potential to regulate multiple signalling pathways in cells, and that tamoxifen is an already approved drug, our results suggest that repurposing tamoxifen to mechanically reprogram the tumour microenvironment may lead to new strategies in cancer therapeutics.

 

Article 1

Link: https://www.embopress.org/doi/10.15252/embr.201846557

Journal: EMBO Rep (2019)20:e46557

Title: Tamoxifen mechanically reprograms the tumor microenvironment via HIF‐1A and reduces cancer cell survival

Abstract:

The tumor microenvironment is fundamental to cancer progression, and the influence of its mechanical properties is increasingly being appreciated. Tamoxifen has been used for many years to treat estrogen‐positive breast cancer. Here we report that tamoxifen regulates the level and activity of collagen cross‐linking and degradative enzymes, and hence the organization of the extracellular matrix, via a mechanism involving both the G protein‐coupled estrogen receptor (GPER) and hypoxia‐inducible factor‐1 alpha (HIF‐1A). We show that tamoxifen reduces HIF‐1A levels by suppressing myosin‐dependent contractility and matrix stiffness mechanosensing. Tamoxifen also downregulates hypoxia‐regulated genes and increases vascularization in PDAC tissues. Our findings implicate the GPER/HIF‐1A axis as a master regulator of peri‐tumoral stromal remodeling and the fibrovascular tumor microenvironment and offer a paradigm shift for tamoxifen from a well‐established drug in breast cancer hormonal therapy to an alternative candidate for stromal targeting strategies in PDAC and possibly other cancers.

 

 

Figure legend: Tamoxifen remodels the tumour microenvironment, reduces the response to hypoxia, and increases vascularization in mouse models of pancreatic cancer. Figure taken from2.

 

Article 2:

Link: https://www.embopress.org/doi/10.15252/embr.201846556

Journal: EMBO  Rep (2019)20:e46556

Title: GPER is a mechanoregulator of pancreatic stellate cells and the tumor microenvironment

Abstract:

The mechanical properties of the tumor microenvironment are emerging as attractive targets for the development of therapies. Tamoxifen, an agonist of the G protein‐coupled estrogen receptor (GPER), is widely used to treat estrogen‐positive breast cancer. Here, we show that tamoxifen mechanically reprograms the tumor microenvironment through a newly identified GPER‐mediated mechanism. Tamoxifen inhibits the myofibroblastic differentiation of pancreatic stellate cells (PSCs) in the tumor microenvironment of pancreatic cancer in an acto‐myosin‐dependent manner via RhoA‐mediated contractility, YAP deactivation, and GPER signaling. This hampers the ability of PSCs to remodel the extracellular matrix and to promote cancer cell invasion. Tamoxifen also reduces the recruitment and polarization to the M2 phenotype of tumor‐associated macrophages. Our results highlight GPER as a mechanical regulator of the tumor microenvironment that targets the three hallmarks of pancreatic cancer: desmoplasia, inflammation, and immune suppression. The well‐established safety of tamoxifen in clinics may offer the possibility to redirect the singular focus of tamoxifen on the cancer cells to the greater tumor microenvironment and lead a new strategy of drug repurposing.

 

 

Article 3:

Link: https://www.nature.com/articles/s41388-018-0631-3

Link to a video abstract: https://www.youtube.com/watch?v=IxEnjZ3GfsA&feature=youtu.be

Journal: Oncogene volume 38, pages2910–2922 (2019)

Title: Tamoxifen mechanically deactivates hepatic stellate cells via the G protein-coupled estrogen receptor.

Abstract:

Tamoxifen has been used for many years to target estrogen receptor signalling in breast cancer cells. Tamoxifen is also an agonist of the G protein-coupled estrogen receptor (GPER), a GPCR ubiquitously expressed in tissues that mediates the acute response to estrogens. Here we report that tamoxifen promotes mechanical quiescence in hepatic stellate cells (HSCs), stromal fibroblast-like cells whose activation triggers and perpetuates liver fibrosis in hepatocellular carcinomas. This mechanical deactivation is mediated by the GPER/RhoA/myosin axis and induces YAP deactivation. We report that tamoxifen decreases the levels of hypoxia-inducible factor-1 alpha (HIF-1α) and the synthesis of extracellular matrix proteins through a mechanical mechanism that involves actomyosin-dependent contractility and mechanosensing of tissue stiffness. Our results implicate GPER-mediated estrogen signalling in the mechanosensory-driven activation of HSCs and put forward estrogenic signalling as an option for mechanical reprogramming of myofibroblast-like cells in the tumour microenvironment. Tamoxifen, with half a century of safe clinical use, might lead this strategy of drug repositioning.

 

 

Figure legend: Tamoxifen mechanically deactivates hepatic stellate cells by inhibiting actomyosin contractility. This modulates mechanosensing, the ability of cells to apply forces on their surroundings and to respond to the lack of oxygen. Figure was taken from1.

 

References:

  1. Cortes, E.; Lachowski, D.;  Rice, A.;  Thorpe, S. D.;  Robinson, B.;  Yeldag, G.;  Lee, D. A.;  Ghemtio, L.;  Rombouts, K.; Del Rio Hernandez, A. E., Tamoxifen mechanically deactivates hepatic stellate cells via the G protein-coupled estrogen receptor. Oncogene 2018.
  2. Cortes, E.; Lachowski, D.;  Robinson, B.;  Sarper, M.;  Teppo, J. S.;  Thorpe, S. D.;  Lieberthal, T. J.;  Iwamoto, K.;  Lee, D. A.;  Okada-Hatakeyama, M.;  Varjosalo, M. T.; Del Rio Hernandez, A. E., Tamoxifen mechanically reprograms the tumor microenvironment via HIF-1A and reduces cancer cell survival. EMBO reports 2019, 20 (1).
  3. Cortes, E.; Sarper, M.;  Robinson, B.;  Lachowski, D.;  Chronopoulos, A.;  Thorpe, S. D.;  Lee, D. A.; Del Rio Hernandez, A. E., GPER is a mechanoregulator of pancreatic stellate cells and the tumor microenvironment. EMBO reports 2019, 20 (1).