Basal cytokeratins and their relationship to the cellular origin and functional classification of breast cancer

Human breast cancers are heterogeneous in their morphology, response to therapy and clinical course. This heterogeneity may originate in differences in the underlying target cell population and/or it may be the result of different combinations of oncogene activation and loss of tumour suppressor gene function in a normal breast stem cell or committed progenitor. The concept of breast cancer stem cells and their relationship to kinetics in the normal breast was excellently reviewed by Behbod and Rosen [1]. The present review focuses on the characterization of the epithelium of the normal human breast and on what we know about the origin of breast cancer from morphological and cell biological viewpoints. Recent expression profiling data are considered within the context of this experimental classification of normal and neoplastic breast tissue, and of how these two valuable approaches are coming together to develop a new functional classification with predictive value for clinical behaviour and response to targeted therapies. In a recent commentary in this journal, Wilson and Dering [2] reviewed the current position in integrating available microarray data in relation to pathway signatures, with an emphasis on endocrine response. This review focuses on how these data relate to our limited knowledge of the cell-type origin of breast cancer.From 28 weeks of intrauterine life the normal human breast is composed of two cell layers, an inner luminal cell population and a distinct outer cell layer, juxtaposed to the basement membrane, termed the 'basal' layer [3]. Although the breast ductal system is comprised of domains with distinct morphology and function, this layered architecture is found throughout the mammary gland from the nipple to the terminal alveoli. This basal cell layer is morphologically heterogeneous in that cells appear either spindle-shaped or cuboidal, depending on their location in the branching structure of breast ducts and on the hormonal or menopausal