Sex hormone-binding globulin as a context-dependent regulator of sex steroid bioavailability in cancers

Sex hormone-binding globulin (SHBG) is a hepatocyte-derived glycoprotein that regulates systemic sex steroid bioavailability and thereby modulates tissue access to androgens and estrogens. Defining SHBG function in vivo has been challenging because mice lack circulating SHBG after birth, leading the field to rely largely on correlative clinical studies and in vitro systems with limited physiological context. The development of human SHBG-transgenic mice has provided a tractable platform to test causal roles of SHBG in sex steroid-related cancers under physiologically relevant endocrine conditions. Recent in vivo studies using this model indicate that SHBG can restrain hepatocellular carcinoma (HCC) progression in specific contexts, including androgen-dominant settings in males and fatty liver-accelerated HCC in postmenopausal females, while other hormonal milieus (e.g., postmenopausal females under normal chow or synthetic estrogen exposure in males) can instead be associated with accelerated tumor progression. In addition, ovariectomized HCC and spontaneous breast cancer model suggests that SHBG can suppress tumor growth or metastasis in a sex hormone-independent manner. Collectively, evidence supports SHBG as a context-dependent regulator of tumor biology through both modulation of sex steroid availability and hormone-independent mechanisms that influence tumor-promoting signaling. Defining these mechanisms may enable SHBG to be leveraged as a biomarker and therapeutic target for sex hormone endocrine dysregulation or -related cancers.