Derivation of Myoepithelial Progenitor Cells from Bipotent Mammary Stem/Progenitor Cells

Xiangshan Zhao,Vimla Band,Hamid Band,Gautam K Malhotra,Fazlul H Sarkar

doi:10.1371/journal.pone.0035338

Abstract

There is increasing evidence that breast and other cancers originate from and are maintained by a small fraction of stem/progenitor cells with self-renewal properties. Recent molecular profiling has identified six major subtypes of breast cancer: basal-like, ErbB2-overexpressing, normal breast epithelial-like, luminal A and B, and claudin-low subtypes. To help understand the relationship among mammary stem/progenitor cells and breast cancer subtypes, we have recently derived distinct hTERT-immortalized human mammary stem/progenitor cell lines: a K5+/K19− type, and a K5+/K19+ type. Under specific culture conditions, bipotent K5+/K19− stem/progenitor cells differentiated into stable clonal populations that were K5−/K19− and exhibit self-renewal and unipotent myoepithelial differentiation potential in contrast to the parental K5+/K19− cells which are bipotent. These K5−/K19− cells function as myoepithelial progenitor cells and constitutively express markers of an epithelial to mesenchymal transition (EMT) and show high invasive and migratory abilities. In addition, these cells express a microarray signature of claudin-low breast cancers. The EMT characteristics of an un-transformed unipotent mammary myoepithelial progenitor cells together with claudin-low signature suggests that the claudin-low breast cancer subtype may arise from myoepithelial lineage committed progenitors. Availability of immortal MPCs should allow a more definitive analysis of their potential to give rise to claudin-low breast cancer subtype and facilitate biological and molecular/biochemical studies of this disease.

Highlights

The epithelial compartment of the mammary gland is composed of two types of cells, luminal cells that line the ductal tree and form the secretory epithelial cells within the alveoli of a lactating mammary gland, and outer myoepithelial cells that border the basal lamina separating epithelial cells from the extracellular matrix
Certain findings suggest that myoepithelial cells play a role in suppressing mammary oncogenesis: i) myoepithelial cells have been shown to secrete a number of suppressor proteins that limit cancer cell growth and invasiveness [4,5]; ii) compared to the frequency of human breast cancers that share features of luminal cells, neoplasms of apparent myoepithelial origin, such as myoepithelioma [6] or metaplastic tumors [7], are extremely rare
K19+) of hTERT-immortalized human mammary stem/progenitor cell lines, both of which exhibit marker profiles of bipotent mammary stem/progenitor cells, and demonstrate the abilities of self-renewal as well as differentiation into luminal and myoepithelial cells when cultured under appropriate culture conditions [19]

Summary

Introduction

The epithelial compartment of the mammary gland is composed of two types of cells, luminal cells that line the ductal tree and form the secretory epithelial cells within the alveoli of a lactating mammary gland, and outer myoepithelial cells that border the basal lamina separating epithelial cells from the extracellular matrix. The relationship of luminal epithelial cells with breast cancer has received considerable attention as tumor cells in most human breast cancers share features of luminal cells. Certain findings suggest that myoepithelial cells play a role in suppressing mammary oncogenesis: i) myoepithelial cells have been shown to secrete a number of suppressor proteins that limit cancer cell growth and invasiveness [4,5]; ii) compared to the frequency of human breast cancers that share features of luminal cells, neoplasms of apparent myoepithelial origin, such as myoepithelioma [6] or metaplastic tumors [7], are extremely rare. Previous expression profiling studies have further expanded the concept of clinical heterogeneity and identified five major subtypes of breast cancer: basal epithelial-like, ErbB2-overexpressing, normal breast epithelial-like and two luminal (luminal A and B) subtypes [9,10,11]. Analyses of patient survival have shown significantly different outcomes for patients belonging to various subtypes [9,11]

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Conclusion