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Stem cells and breast cancer: A field in transit

Nature Reviews Cancer volume 3, pages 832–844 (2003)Cite this article

Key Points

  • Stem cells have a long life and a large replicative potential, making them good candidates for the cells of origin of cancer.

  • The adult mammary gland requires stem cells, or a stem-cell-like activity, to fulfil the demands of pregnancy-dependent epithelial expansion and replace cells that are lost through routine cell turnover.

  • Evidence for the existence of specialized adult mammary stem cells comes from transplantation, retroviral tagging and X-chromosome-linked gene-inactivation studies.

  • Current evidence points to an undifferentiated, suprabasal cell, with a slow proliferative rate that has characteristics in common with stem cells from other tissues, as the best candidate for an adult mammary epithelial stem cell.

  • Experimental evidence from the transplantation of tumour-cell subpopulations and from animal models supports the view that breast stem cells are the cells in which mammary cancers are initiated.

  • Therapeutic or prophylactic targeting of breast stem cells provides a novel approach to breast cancer treatment that is aimed directly at the cells of origin of the tumour.

Abstract

Evidence that supports the existence of a tumour stem cell for breast cancer has given fresh impetus to the search for an adult mammary epithelial stem cell in the normal breast. Such a cell might be responsible for routine tissue renewal and the massive expansion in epithelial tissue that the breast undergoes during pregnancy, and might be the cell of origin of most, if not all, breast tumours. So, what evidence is there that an adult mammary epithelial stem cell exists, what is its possible identity and what opportunities might the identification of such a cell present for the development of novel therapeutic and prophylactic strategies for treating breast cancer?

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Figure 1: The human breast and rodent mammary gland.
Figure 2: The terminal end bud.
Figure 3: The role of stem cells in the adult mammary gland.
Figure 4: Field cancerization.

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Acknowledgements

The authors would like to acknowledge all those who have contributed to this field but whose work could not be included due to space constraints. The authors would also like to thank G. Chepko for access to unpublished material and all those who have critically read this manuscript and offered suggestions for its improvement. Work in the authors' laboratory is funded by Breakthrough Breast Cancer and Cancer Research UK.

Author information

Authors and Affiliations

  1. The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, Fulham Road, London, SW3 6JB, UK

    Matthew Smalley & Alan Ashworth

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  1. Matthew Smalley
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  2. Alan Ashworth
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Corresponding author

Correspondence to Alan Ashworth.

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DATABASES

Cancer.gov

breast cancer

LocusLink

KIP1

ESA

MUC1

CD10

integrin-α6

cytokeratin 19

SCA1

ABCG2

CD44

CD24

BRCA2

TP53

syndecan 1

FURTHER INFORMATION

The Biology of the Mammary Gland home page

Breakthough Breast Cancer

The Breakthrough Centre

The Stem Cell Database

Glossary

TERMINAL DIFFERENTIATION

The process by which stem-cell or transit-amplifying-cell progeny commit to becoming the mature, fully functioning cell type of a tissue. Probably irreversible.

MICROENVIRONMENT

The local growth conditions of the cell, formed by interactions between the extracellular matrix, blood supply, local cell types, and circulating hormones and growth factors.

LUMINAL EPITHELIAL CELLS

The cells that line the lumen — also used to refer to the non-myoepithelial component of the mammary epithelium in general.

MYOEPITHELIAL CELLS

Contractile cells that form a basket-like network around the secretory alveoli and a sheath around the ducts. These squeeze the milk down the ducts and out of the nipple in response to the hormone oxytocin.

APOPTOSIS

Programmed cell death that is characterized by regulated DNA digestion and phagocytosis of cell debris with minimal tissue inflammation.

LUMEN

The space in the centre of the mammary ducts and alveoli into which milk is secreted, and along which it passes to the nipple.

SECRETORY ALVEOLI

Structures that resemble bunches of grapes in the mammary epithelium that produce milk products. They are few in number in the virgin or non-parous animal, but appear in huge numbers during pregnancy and fill the gland during lactation.

INVOLUTION

The name given to the process of apoptosis and tissue remodelling by which the mammary gland changes from the epithelial-cell-rich lactational state to the epithelial-cell-sparse non-parous state following weaning of offspring.

ADIPOSE MATRIX

The fatty connective tissue of the mammary gland that supports the epithelium.

RETROVIRAL TAGGING

Uses retroviral infection of cells as a lineage marker to enable the progeny of marked cells to be followed over many generations. Retroviral sequences incorporated into host DNA are detected by Southern blotting, and common insertion patterns are used to infer lineage relationships.

X-CHROMOSOME INACTIVATION

The process by which one X chromosome is stably transcriptionally inactivated. This occurs in almost all mammalian female (XX) cells to achieve comparable gene dosage to XY males.

MAMMARY TREE

The complete epithelial structure of the mammary gland that, with its branching ducts and associated alveoli, resembles the branching of a tree.

TERMINAL DUCTAL LOBULO-ALVEOLAR UNITS

(TDLUs). The structures in the human breast that are equivalent to the secretory alveoli of the rodent. They have a higher order of organization than rodent alveoli, and consist of alveoli that are clustered around a distinct duct and ductal side branches. They also have a distinctive stromal component — the intralobular fibroblasts — as opposed to the interlobular fibroblasts of the breast connective tissue.

HISTOLOGY

The analysis of tissue samples by routine pathological methods and light microscopy.

ULTRASTRUCTURE

Cell and tissue morphology at the electron-microscope level.

CYTOKERATIN

A structural cellular protein that is typical of epithelia.

XENOGRAFTS

The growth of primary human tissue, cancer cells or cancer cell lines in animal hosts in an attempt to recapitulate aspects of normal, or cancerous, cell growth and morphology.

MAMMOSPHERES

Balls of mammary epithelial cells that form under specialized culture conditions in vitro and that are capable of functional differentiation in the correct hormonal environment. Mammospheres that grow in suspension culture are analogous to neurospheres grown under similar conditions.

ABC TRANSPORTER PROTEINS

Transmembrane protein pumps that can eliminate various small molecules from the cell.

POST-TRANSPLANT BONE-MARROW RECONSTITUTING ACTIVITY

The ability of bone-marrow cells, transplanted into an animal that has received lethal whole-body irradiation, to regenerate the haematopoietic stem-cell compartment and keep the animal alive.

CHIMERIC

Composed of cells that originate from more than one source.

LOSS OF HETEROZYGOSITY

The elimination of the remaining normal copy of a gene from a cell that already carries one mutant copy of that gene. This results in the complete loss of function of the gene from that cell.

PROPHYLACTIC

Preventative treatment.

HEPARAN-SULPHATE PROTEOGLYCANS

Cell-surface molecules that might have a role in regulating cell–matrix or receptor–ligand interactions.

WNT1

A potent mammary oncoprotein that is activated by the mouse mammary tumour virus. Its normal role is as a developmental regulator.

RNA INTERFERENCE

A technique that triggers a natural defence mechanism against certain viruses and tricks the cells into suppressing expression of endogenous genes.

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Smalley, M., Ashworth, A. Stem cells and breast cancer: A field in transit. Nat Rev Cancer 3, 832–844 (2003). https://doi.org/10.1038/nrc1212

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