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Simple Summary  Here we investigated the most aggressive type of breast cancer (triple negative breast cancer (TNBC)) for which no effective therapies exist. Modulated electro-hyperthermia (mEHT) utilizes the altered bioelectric properties of tumors to implement a selective energy-transmission of an electromagnetic field and induce thermal and non-thermal anti-tumor effects. In our present study, repeated mEHT treatment effectively inhibited growth and proliferation and caused significant, destruction of TNBC tumors when applied alone without any other therapy in mice. Immunohistochemistry and multiplex analysis revealed that mEHT treatment induced protective mechanisms, like upregulation of heat shock proteins and other stress-related genes. Inhibition of these factors may serve as therapeutic approach to enhance the efficacy of mEHT. We were able to inhibit one of these protective proteins in cell culture. We aim to study the possibility of enhancing mEHT and other cancer therapies by inhibiting the identified protective stress response.    Abstract  Modulated electro-hyperthermia (mEHT) is a selective cancer treatment used in human oncology complementing other therapies. During mEHT, a focused electromagnetic field (EMF) is generated within the tumor inducing cell death by thermal and nonthermal effects. Here we investigated molecular changes elicited by mEHT using multiplex methods in an aggressive, therapy-resistant triple negative breast cancer (TNBC) model. 4T1/4T07 isografts inoculated orthotopically into female BALB/c mice were treated with mEHT three to five times. mEHT induced the upregulation of the stress-related Hsp70 and cleaved caspase-3 proteins, resulting in effective inhibition of tumor growth and proliferation. Several acute stress response proteins, including protease inhibitors, coagulation and heat shock factors, and complement family members, were among the most upregulated treatment-related genes/proteins as revealed by next-generation sequencing (NGS), Nanostring and mass spectrometry (MS). pathway analysis demonstrated that several of these proteins belong to the response to stimulus pathway. Cell culture treatments confirmed that the source of these proteins was the tumor cells. The heat-shock factor inhibitor KRIBB11 reduced mEHT-induced complement factor 4 (C4) mRNA increase. In conclusion, mEHT monotherapy induced tumor growth inhibition and a complex stress response. Inhibition of this stress response is likely to enhance the effectiveness of mEHT and other cancer treatments.

Modulated Electro-Hyperthermia Induces a Prominent Local Stress Response and Growth Inhibition in Mouse Breast Cancer Isografts