Research
Structural determinants of sex hormone signaling
How can key differentiation factors in sexual development moonlight as oncogenes?
Sex steroids are hormones that play important roles during all stages of life – from development in utero to puberty, maintenance of fertility and sex characteristics during adulthood, and even cancer onset in old age.
To function, sex steroids bind to and activate their corresponding steroid receptors, which in turn facilitate transcription of genes that govern different life stages. For instance, male sex steroids (androgens) bind to and can activate the androgen receptor to promote prostate and muscle growth during development, and prostate cancer in the aged. Conversely, the female sex steroids (estrogens and progesterones) recognize the estrogen and progesterone receptors to promote breast growth and menstruation, but are also drivers of breast, ovarian and uterine cancers.
Research in the Wasmuth Laboratory focuses on understanding the discrete signals that allow a common steroid receptor to function as both a differentiation factor and an oncogene. We hypothesize that this duality can be influenced by structural changes within the receptor itself. We employ a multidisciplinary approach of biochemistry, structural biology, molecular biology, and cancer biology.
Using single particle cryo-electron microscopy, we recently discovered that the androgen receptor is endowed with unique shape-shifting features that readily permit promiscuous binding to DNA in collaboration with oncoprotein cofactors.
We demonstrated that this interaction can contribute to androgen receptor’s oncogenicity in the context of advanced prostate cancer. Implications of this and ongoing work in the lab will lay the foundation for development of more effective steroid receptor targeting agents in disease.
Collaborators
We have a range of collaborators from chemists to clinicians across the US.
