CD44 expression and regulation during mammary gland development and function

The CD44v6 epitope has been widely reported to be expressed in human mammar y carcinomas, yet its prognostic significance is controversial and its func tion in mammary tnmors and mammary glands is unknown. To begin to resolve t hese issues, we analysed in detail the normal postnatal expression patterns and regulation of the CD44v6 epitope in murine mammary glands. We demonstr ate that significant CD44v6 epitope expression is first seen during puberty , and that after puberty CD44v6 epitope expression follows the estrous cycl e. CD44v6 epitope expression is observed in the myoepithelium and also less widely in luminal epithelial cells. During lactation, CD44v6 epitope expre ssion is turned off and reappears during involution, The CD44 variant isofo rm bearing the v6 epitope is CD44v1-v10. Using HC11, a mammary epithelial c ell line with stem cell characteristics, and facilitated by the cloning of the murine CD44 promoter, we show that growth factors and hormones which re gulate ductal growth and differentiation modulate CD44 transcription. Toget her our data suggest that the CD44v6 epitope is expressed in mammary epithe lial stems cells and in lineages derived from these cells, and that CD44v6 expression is regulated in part by hormones and growth factors such as IGF- 1 and EGF which regulate the growth and differentiation of the mammary epit helium, The function of these same growth factors and hormones is often per turbed in mammary carcinomas, and we suggest that CD44v6 expression in tumo rs reflects this perturbation. We conclude that the expression of the CD44v 6 epitope observed in some mammary tumors reflects the stem cell origin of breast tumors, and that whether or not the CD44v6 epitope is expressed in a mammary tumor is determined by the differentiation status of the tumor cel ls.