An Increase in HSF1 Expression Directs Human Mammary Epithelial Cells toward a Mesenchymal Phenotype

Simple Summary Epithelial, compactly packed cells form a protective layer lining the surfaces of organs and cavities throughout the body. They can lose their features and gain migratory and invasive (mesenchymal) properties. This epithelial-to-mesenchymal transition (EMT) is essential for numerous developmental processes and wound healing but can also cause organ fibrosis and metastasis initiation in cancer progression. We found that the heat shock transcription factor 1 (HSF1), commonly activated by environmental stress, may contribute to EMT in the human mammary epithelial cells. Moreover, elevated HSF1 levels correlate with invasive features of breast cancer cells, and the use of the HSF1 inhibitor DTHIB significantly inhibits their growth. We postulate that HSF1 may be involved in the remodeling of the mammary gland architecture over the female lifetime, as well as the acquisition of invasive cancer cell phenotype. Therefore, HSF1 inhibition could be tested as an adjuvant treatment for breast cancer patients.Abstract HSF1 is a well-known heat shock protein expression regulator in response to stress. It also regulates processes important for growth, development or tumorigenesis. We studied the HSF1 influence on the phenotype of non-tumorigenic human mammary epithelial (MCF10A and MCF12A) and several triple-negative breast cancer cell lines. MCF10A and MCF12A differ in terms of HSF1 levels, morphology, growth in Matrigel, expression of epithelial (CDH1) and mesenchymal (VIM) markers (MCF10A are epithelial cells; MCF12A resemble mesenchymal cells). HSF1 down-regulation led to a reduced proliferation rate and spheroid formation in Matrigel by MCF10A cells. However, it did not affect MCF12A proliferation but led to CDH1 up-regulation and the formation of better organized spheroids. HSF1 overexpression in MCF10A resulted in reduced CDH1 and increased VIM expression and the acquisition of elongated fibroblast-like morphology. The above-mentioned results suggest that elevated levels of HSF1 may direct mammary epithelial cells toward a mesenchymal phenotype, while a lowering of HSF1 could reverse the mesenchymal phenotype to an epithelial one. Therefore, HSF1 may be involved in the remodeling of mammary gland architecture over the female lifetime. Moreover, HSF1 levels positively correlated with the invasive phenotype of triple-negative breast cancer cells, and their growth was inhibited by the HSF1 inhibitor DTHIB.

Automated summary

Epithelial-to-mesenchymal transition (EMT) is important for development and wound healing, but can also contribute to organ fibrosis and cancer metastasis. This study suggests that the heat shock transcription factor 1 (HSF1) may be involved in EMT in human mammary epithelial cells, and inhibiting HSF1 could potentially be a treatment for breast cancer.