From Tissue Integrity to Tumor Plasticity: HSF2 in Human Physiology and Breast Cancer Progression

Cells are constantly exposed to extrinsic and intrinsic stressors that challenge protein homeostasis, i.e., proteostasis. To withstand proteotoxic stress, cells rely on an intact proteostasis network that coordinates protein synthesis, folding, and degradation. Beyond stress protection, this network is essential for organismal homeostasis by supporting early development and differentiation-related events as well as adult tissue remodeling, integrity, and repair. On the molecular level, heat shock transcription factors (HSFs) have emerged as central regulators of the proteostasis network, inducing the expression of molecular chaperones to sustain proteome integrity. While HSFs have been extensively studied in the context of acute heat shock and development, how they contribute to human tissue physiology has remained
largely uncovered. When proteostasis is chronically compromised, proteotoxic stress accumulates and predisposes to a range of diseases, including cancer. In breast cancer, HSF1 is a well-established driver of malignancy, promoting tumor progression through hyperactivation of molecular chaperones and induction of cancer-specific gene programs. HSF2 has also been associated with breast carcinogenesis, but the underlying regulatory mechanisms and its function during the different stages of breast cancer progression has remained unknown.

The first study of this thesis provides a comprehensive atlas of HSF1 and HSF2 expression and subcellular localization across a large set of benign human tissues. HSF1 was abundantly expressed in the nucleus and cytoplasm of cells across the examined tissues, suggesting fundamental and constitutive functions in the maintenance of tissue homeostasis. In contrast, HSF2 displayed a unique expression pattern, localizing to the cytoplasm of smooth muscle cells, to the nucleus of specific proliferative and barrier-facilitating cells, and at distinct cell-cell adhesion sites. The results indicate that HSF2 has cell and tissue type-specific functions and is potentially contributing to tissue integrity and barrier function by regulating adhesion networks. The second study of this thesis focused on delineating the function of HSF2 in breast
cancer progression. By combining the analysis of human tissue samples with cell-based in vitro and in vivo models as well as genome-wide transcriptomics, we found that HSF2 acts as a molecular switch between proliferation and invasion in breast cancer. High levels of nuclear HSF2 denoted a hyperplastic cell state underlying pre-invasive tumor expansion, whereas the invasive transition was accompanied by a temporal downregulation or cytoplasmic retention of HSF2. Altogether, the results of this thesis demonstrate that HSF1 and HSF2 are integrated into the organization and plasticity of human tissues, from physiological homeostasis to malignant transformation.