Amphiregulin mediates progesterone-induced mammary ductal development during puberty.
Aupperlee MD, Leipprandt JR, Bennett JM, Schwartz RC, Haslam SZ.
Michigan State University, Lansing, MI.
Breast Cancer Research, 2013 May 25;15(3):R44.
Introduction: Puberty is a period of increased sensitivity to factors that increase breast cancer risk in adulthood. During puberty unique structures called end buds (EB) are the major site for producing growth of the mammary gland. EB, present only during pubertal development, are believed to be sites where breast cancers start. The role of the hormone estrogen (E) has been extensively studied in pubertal EB formation and mammary gland growth. While a role for progesterone (P) has been identified in promoting postmenopausal breast cancer, the role of P during puberty is less defined. This study examines the mechanism of P involvement in pubertal mammary gland development.
Methods: Pubertal and pre-pubertal mice had their ovaries removed to stop normal hormone production, and were then treated with control, E, P, or E+P. Mammary glands from these mice were analyzed for changes in size and structures , such as EB formation, and for the production of factors produced by P that promote EB formation and growth such as amphiregulin (AREG) and Receptor Activator of NF-kB Ligand (RANKL).
Results: P, acting specifically through the progesterone receptor, stimulated EB formation and mammary gland growth. These changes were associated with increased mammary gland production of AREG Blocking AREG action with an inhibitor completely blocked the effect of P on EB formation and mammary gland growth. E, acting specifically through the estrogen receptor, produced similar effects on EB formation and mammary gland growth also through production of AREG. P also increased expression of RANKL, and treatment with an inhibitor of RANKL reduced P-dependent mammary gland growth but to a lesser extent that by inhibiting AREG.
Conclusions: These results demonstrate a novel P-specific effect through AREG to cause EB formation and mammary gland growth both prior to and during puberty. Thus, hormones and/or factors in addition to E that increase AREG can promote EB formation and mammary gland growth and these factors have the potential to affect breast cancer risk associated with pubertal mammary gland development.