Breast cancer is the most common tumor diagnosed in women. The majority of cases are estrogen receptor α positive (ER+). The lack of relevant in vivo models hampers the study of the pathogenesis of ER+ breast cancer cells and the finding of the possible way for drug treatment. The recently developed mouse intraductal (MIND) model, based on the breast cancer cell injection directly into the mouse milk duct system, provides an intraductal microenvironment adequate for ER+ breast cancer cell growth and enables the recapitulation of human disease. We use the MIND model to study the role of HSF1 inhibition in ER+ breast cancer growth. HSF1 plays a key role in the cell response to stress and also supports many aspects of cell metabolism enabling tumor growth. We found that HSF1 is activated by 17β-estradiol (E2) in ER+ breast cancer cells and gains transcriptional competence to regulate the expression of several genes associated with E2 signaling. HSF1 deficiency reduces the growth of ER+ cells in vitro and may be a potential target for breast cancer treatment.

The human breast adenocarcinoma MCF7-Luc2 cells expressing luciferase were knockouted for HSF1 using the CRISPR/Cas9 editing system. The growth of MCF7-Luc2 cells HSF1-deficient or HSF1-proficient was analyzed in vitro. Tumor cells were injected into the ductal system of NSG (NOD scid gamma) mice. The tumor growth was monitored through bioluminescence imaging (IVIS system).

The complete lack of HSF1 led to a substantial loss of heat-inducibility of HSP genes (molecular target of HSF1) and a reduction of the proliferation rate of MCF7-Luc2 cells in vitro. After injection of MCF7-Luc2 cells with different HSF1 status into the abdominal mammary gland of adult female NSG mice, they grew without hormonal supplementation for 6 months. In vivo monitoring of engrafting mice by luminescence revealed that all cell lines grew exponentially, but the growth of HSF1-deficient MCF7-Luc2 cells was slowed down compared to HSF1-proficient cells.

The MIND model offers the opportunity to study the progression of ER+ breast cancer and the role of HSF1 in its development. It can be used to test new combination therapies targeting HSF1 and estrogen receptors. The work was supported by the National Science Center, grant no. 2021/43/B/NZ5/01850