Abstract 5114: The role of amphiregulin in mammary gland development and breast cancer
Authors: Mao Serena , Park Minji , Cabrera Ramon , Christin John , Karagiannis George , Guo Wenjun , Condeelis John , Segall Jeffrey 
Published: August 2018

Breast cancer is the most prevalent cancer in women worldwide and afflicts more than 3.1 million women in the US alone. The epidermal growth factor receptor (EGFR) is frequently overexpressed in breast cancer and is associated with poor clinical outcome. Several therapies involving anti-EGFR agents have been developed to target breast cancer. However, clinical trials have shown mixed outcomes with these therapies. Amphiregulin (AREG), a ligand of the epidermal growth factor receptor (EGFR), is enriched in invasive breast cancer, particularly ERα-positive breast tumors. In normal physiology, AREG mediates estrogen-induced ductal morphogenesis during mammary gland development. In the absence of AREG, the ductal tree fails to elongate and remains rudimentary throughout adulthood. The structure of a healthy mammary duct consists of luminal cells surrounded by a layer of myoepithelial cells. Studies of mammary gland transplantations suggest that a marker of myoepithelial cells (keratin 14, K14) is only expressed if AREG is present in the mammary epithelium. Multiple studies have provided evidence that myoepithelial cells are natural tumor suppressors. During tumor growth, the disappearance of myoepithelial cells indicates progression to invasive carcinoma. Therefore we hypothesize that AREG plays an important role in maintenance of the maintenance of myoepithelial cells in the mammary epithelium and loss of AREG promotes tumor progression as a result of an early loss of myoepithelial cells. In the mammary glands of AREG WT and AREG KO mice without the PyMT transgene, we have found that mammary ducts in AREG KO mice have significantly fewer myoepithelial cells. Immunofluorescent staining of K14 has revealed a thinner and discontinuous myoepithelial layer in the AREG KO mice. To investigate the role of AREG in breast cancer development and progression, we have utilized a spontaneous mammary tumor mouse model where oncogenesis is driven by expression of the polyoma middle T oncoprotein (PyMT) through the mouse mammary tumor virus (MMTV) promoter. We have crossed AREG knockout mice with the MMTV-PyMT mice to generate AREG KO mice that spontaneously form mammary tumors (AREG KO PyMT). The absence of AREG in both the mammary epithelial and stromal compartments accelerates tumor growth. By 12 weeks of age, tumors of AREG KO PyMT mice are significantly larger than that of AREG WT PyMT mice. AREG KO tumors are histologically less necrotic, apoptotic, and progressed than AREG WT tumors. Furthermore, AREG KO tumors show higher staining of PyMT by immunofluorescence. Together, these results suggest that loss of AREG stimulates tumor initiation but inhibits progression due to fewer myoepithelial cells beginning during development.

Citation Format: Serena Mao, Minji Park, Ramon Cabrera, John Christin, George Karagiannis, Wenjun Guo, John Condeelis, Jeffrey Segall. The role of amphiregulin in mammary gland development and breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5114.