Mechanosensitive Steroid Hormone Signaling and Cell Fate

Abstract

Mechanical forces collaborate across length scales to coordinate cell fate during development and the dynamic homeostasis of adult tissues. Similarly, steroid hormones interact with their nuclear and nonnuclear receptors to regulate diverse physiological processes necessary for the appropriate development and function of complex multicellular tissues. Aberrant steroid hormone action is associated with tumors originating in hormone-sensitive tissues and its disruption forms the basis of several therapeutic interventions. Prolonged perturbations to mechanical forces may further foster tumor initiation and the evolution of aggressive metastatic disease. Recent evidence suggests that steroid hormone and mechanical signaling intersect to direct cell fate during development and tumor progression. Potential mechanosensitive steroid hormone signaling pathways along with their molecular effectors will be discussed in this context.

Keywords: cell fate; mechanosensitive; mechanotransduction; reproductive cancers; steroid hormones; tissue mechanics.

Figure 1.

Mechanosensitive hormone signaling associated with ECM remodeling and integrin activity. (1) Estrogen promotes fibronectin bound β1-integrin colocalization with ERα at the cell membrane and endocytic recycling of ERα to the cell surface. (2) Palmitoylated membrane-bound ERα is critical for paracrine signaling to mammary epithelial stem cells, and the expression of fibronectin and MMP9 required for efficient epithelial cell migration and branching morphogenesis. (3) Steroid hormone-induced paracrine Wnt signaling promotes the expression of Adamts18 in myoepithelial cells, which is required for genetic interaction with the basement membrane proteoglycan, Col18a1, and matrix remodeling to generate a mammary stem cell niche. (4) Compressive forces induce p38α MAPK activation in mammary epithelial cells, resulting in inhibition of ERα gene silencing by EZH2-mediated histone methylation. (5) A dense collagen matrix was found to promote the expansion of prolactin induced ERα-positive breast cancer stem cells through elevated Akt/mTOR/YAP signaling. Moreover, estrogen stimulation of prolactin induced ER-positive tumor cells results in more aligned peritumoral collagen and elevated expression of ECM components (fibronectin, tenascin C, maspin, periostin, LOX) associated with breast cancer progression. (6) Elevated ECM stiffness and integrin mechanosignaling may intersect with growth factor signaling to potentiate ERK/MAPK-mediated phosphorylation of PR.

Figure 2.

Mechanosensitive hormone signaling associated with membrane/cytoskeletal dynamics and transcription factor activity. (1) The glycoprotein MUC1 directly interacts with ERα to inhibit its ubiquitination and degradation, and binds with ERα at estrogen-responsive gene promoters to stimulate ERα-mediated transcription. Steroid hormones can also stimulate MUC1 expression. (2) Estrogen induces rapid actin cytoskeleton and membrane remodeling through ERα-Gα13 interactions upstream of RhoA/ROCK/moesin signaling. (3) GPER links estrogen stimulation to PLCβ-PKC and RhoA/ROCK induced actin assembly to drive mechanosensitive TAZ activation and cell migration. GPER can alternatively dampen mechanical stress induced RhoA activity and actin polymerization, resulting in inhibition of apoptosis induced by the mechanosensitive ion channel, Piezo1, as a protective mechanism against cartilage degeneration. (4) RhoA activity is required in PR-expressing luteal cells of the corpus luteum to maintain mitochondrial density, efficient cholesterol transport, and progesterone synthesis. In skeletal muscle cells, mechanical stretch and testosterone stimulation results in increased expression of estrogen-related synthases and estrogen production. (5) WBP2 is a cofactor for ERα/PR and YAP/TAZ transcriptional activity. Wnt signaling suppresses ubiquitin mediated degradation of WBP2 to promote breast cancer progression, whereas phosphorylation of the tumor suppressor, WWOX, triggers its binding to WBP2 to inhibit ERα-mediated transcription. Alternatively, mechanosensitive tyrosine kinase signaling can phosphorylate WBP2 to enhance ERα-mediated transcription. (6) As observed for YAP/TAZ, the intrinsically disordered regions of hormone receptors (AR/PR) could allow for mechanosensitive phase separation and condensate formation to govern hormone-induced transcriptional complex activity.