Sex hormone-binding globulin dampens growth and metastasis of breast cancer in an estrogen-independent manner

Early studies have shown that sex hormone-binding globulin (SHBG) suppresses breast cancer by decreasing estrogen activity. However, the sex hormone-independent role of SHBG in breast cancer has received limited attention. Building on our previous research linking SHBG with tumor-associated macrophage (TYRO3, AXL, and MerTK) receptors, we aimed to explore SHBG's sex hormone-independent involvement in breast cancer progression. Analysis of public datasets and tumor slides from patients with breast cancer revealed that invasive breast cancer was associated with a significant decrease in SHBG, and lower SHBG levels correlated with poor cancer prognosis. In the polyomavirus middle T antigen overexpression mouse model (MMTV-PyMT), SHBG-Tg mice exhibited extended survival both under naïve and ovariectomized conditions. Although SHBG-Tg tumors had an estrogenic environment, their growth was suppressed, which correlated with reduced AXL levels. SHBG plasma treatment inhibited proliferation, tumorsphere growth, and invasion in MDA-MB-231 cells, accompanied by a decrease in AXL levels. In subcutaneous allograft models, SHBG-Tg mice showed reduced tumor growth and metastasis, and intraperitoneal injection of SHBG plasma significantly delayed tumor progression in PyMT mice compared with WT plasma. In summary, our study highlights SHBG's inhibitory role in breast cancer growth and metastasis, which may be particularly relevant for estrogen-independent patients with triple-negative breast cancer.<b>NEW & NOTEWORTHY</b> Our study is the first in vivo experiment using polyomavirus middle T antigen-sex hormone-binding globulin (PyMT-SHBG) mouse model to assess the physiological role of SHBG in breast cancer development. We show that SHBG presence in PyMT model restrains breast cancer development and progression in sex hormone-independent manner.