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Background <p>Contact inhibition regulates cell proliferation via E-cadherin and the Hippo pathway, the dysregulation of which contributes to breast cancer; while physical exercise correlates negatively with breast cancer risk, our study proposes high-intensity interval training (HIIT) as a potential modulator of Hippo signaling to mitigate tumorigenesis, explored through experimental models.</p> Methods <p>Healthy control (CTL), breast cancer (BC), healthy exercise (Ex), and cancer with exercise (BC + Ex) were the four groups into which 48 BALB/c female mice were randomly assigned. Mouse breast cancer cells (4T1) were orthotopically injected into all other groups except the CTL and Ex groups. On a treadmill, the Ex and BC + Ex groups ran for 4–10 periods at 80–100% of their maximal velocity (Vmax). Western blot analysis was used to evaluate neurofibromatosis type II (NF2), macrophage-stimulating 1 (MST1/2), large tumor suppressor kinase 1/2(LATS1/2), transcriptional enhancer factor (TEAD), vestigial-like family member 4 (VGLL4), epidermal growth factor receptor tyrosine kinase (EGFR), E-cadherin, α-catenin, β-catenin, kidney and brain expressed protein (Kibra), yes-associated protein (YAP), and transcriptional coactivator with a PDZ-bindingdomain (TAZ), as well as their phosphorylated forms.</p> Results <p>When compared to the BC group, the BC + Ex group had higher levels of EGFR, E-cadherin, α-catenin, β-catenin, Kibra, NF2, MST1, MST 2, LATS1, LATS 2, P-YAP, VGLL4, and P-TAZ (<i>P</i> &lt; 0.01). Conversely, Ex and BC + Ex had lower levels of YAP, TAZ, and TEAD than CTL and BC (<i>P</i> &lt; 0.01). In addition, tumor volume was lower in BC + Ex compared to BC (<i>P</i> &lt; 0.001).</p> Conclusions <p>Our observations shed light on the potential molecular mechanisms by which exercise influences cancer development and provide insights into novel therapeutic strategies targeting these pathways.</p>

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The therapeutic potential of high-intensity interval training in a breast cancer model: focus on the Hippo signaling pathway

  • 期刊论文

  • 发表日期：

    2025年9月27日

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  • Maryam Hossein Rezaei,
  • Manzumeh Shamsi Meymandi,
  • Amirhossein Moslemizadeh,
  • Elham Madadizadeh,
  • Francisco José Pinto Fraga,
  • Susana López Ortiz,
  • Sajad Haidari,
  • Ladan Langroudi,
  • Mohammad Amin Rajizadeh,
  • Hamideh Bashiri,
  • Kayvan Khoramipour

摘要

Background

Contact inhibition regulates cell proliferation via E-cadherin and the Hippo pathway, the dysregulation of which contributes to breast cancer; while physical exercise correlates negatively with breast cancer risk, our study proposes high-intensity interval training (HIIT) as a potential modulator of Hippo signaling to mitigate tumorigenesis, explored through experimental models.

Methods

Healthy control (CTL), breast cancer (BC), healthy exercise (Ex), and cancer with exercise (BC + Ex) were the four groups into which 48 BALB/c female mice were randomly assigned. Mouse breast cancer cells (4T1) were orthotopically injected into all other groups except the CTL and Ex groups. On a treadmill, the Ex and BC + Ex groups ran for 4–10 periods at 80–100% of their maximal velocity (Vmax). Western blot analysis was used to evaluate neurofibromatosis type II (NF2), macrophage-stimulating 1 (MST1/2), large tumor suppressor kinase 1/2(LATS1/2), transcriptional enhancer factor (TEAD), vestigial-like family member 4 (VGLL4), epidermal growth factor receptor tyrosine kinase (EGFR), E-cadherin, α-catenin, β-catenin, kidney and brain expressed protein (Kibra), yes-associated protein (YAP), and transcriptional coactivator with a PDZ-bindingdomain (TAZ), as well as their phosphorylated forms.

Results

When compared to the BC group, the BC + Ex group had higher levels of EGFR, E-cadherin, α-catenin, β-catenin, Kibra, NF2, MST1, MST 2, LATS1, LATS 2, P-YAP, VGLL4, and P-TAZ (P < 0.01). Conversely, Ex and BC + Ex had lower levels of YAP, TAZ, and TEAD than CTL and BC (P < 0.01). In addition, tumor volume was lower in BC + Ex compared to BC (P < 0.001).

Conclusions

Our observations shed light on the potential molecular mechanisms by which exercise influences cancer development and provide insights into novel therapeutic strategies targeting these pathways.