Stroma in breast development and disease.

It is increasingly apparent that normal and malignant breast tissues require complex local and systemic stromal interactions for development and progression. During development, mammary cell fate specification and differentiation require highly regulated contextual signals derived from the stroma. Likewise, during breast carcinoma development, the tissue stroma can provide tumor suppressing and tumor-promoting environments that serve to regulate neoplastic growth of the epithelium. This review focuses on the role of the stroma as a mediator of normal mammary development, as well as a critical regulator of malignant conversion and progression in breast cancer. Recognition of the important role of the stroma during the progression of breast cancers leads to the possibility of new targets for treatment of the initial breast cancer lesion as well as prevention of recurrence.

[1]  N. Zeps,et al.  Estrogen receptor-negative epithelial cells in mouse mammary gland development and growth. , 1998, Differentiation; research in biological diversity.

[2]  C. Tickle,et al.  Interactions between FGF and Wnt signals and Tbx3 gene expression in mammary gland initiation in mouse embryos , 2004, Journal of anatomy.

[3]  Xiao-Jun Ma,et al.  Gene expression profiling of the tumor microenvironment during breast cancer progression , 2009, Breast Cancer Research.

[4]  Howard Y. Chang,et al.  Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[5]  T. Lyons,et al.  Tamoxifen induces pleiotrophic changes in mammary stroma resulting in extracellular matrix that suppresses transformed phenotypes , 2009, Breast Cancer Research.

[6]  J. Williams,et al.  Mammary ductal elongation: differentiation of myoepithelium and basal lamina during branching morphogenesis. , 1983, Developmental biology.

[7]  G. Merlo,et al.  Stromal influences on transformation of human mammary epithelial cells overexpressing c‐myc and SV40T , 1990, Journal of cellular physiology.

[8]  J. Wysolmerski,et al.  Key stages of mammary gland development: Molecular mechanisms involved in the formation of the embryonic mammary gland , 2005, Breast Cancer Research.

[9]  C. Heldin,et al.  Platelet-derived growth factor (PDGF) in oncogenesis: development of a vascular connective tissue stroma in xenotransplanted human melanoma producing PDGF-BB. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[10]  H. Moses,et al.  Overexpression of a kinase-deficient transforming growth factor-beta type II receptor in mouse mammary stroma results in increased epithelial branching. , 1999, Molecular biology of the cell.

[11]  M. Loeffler,et al.  Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. , 2006, The Journal of clinical investigation.

[12]  W. Ruan,et al.  IGF-I: An Essential Factor in Terminal End Bud Formation and Ductal Morphogenesis , 2004, Journal of Mammary Gland Biology and Neoplasia.

[13]  L. Zon,et al.  Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis , 2007, Nature.

[14]  David Cameron,et al.  A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer , 2009, Nature Medicine.

[15]  J. Thrasher,et al.  Hedgehog signaling promotes prostate xenograft tumor growth. , 2004, Endocrinology.

[16]  M. Barcellos-Hoff,et al.  Irradiated mammary gland stroma promotes the expression of tumorigenic potential by unirradiated epithelial cells. , 2000, Cancer research.

[17]  R. Derynck,et al.  Activation and function of the epidermal growth factor receptor and erbB-2 during mammary gland morphogenesis. , 1998, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[18]  J. Gustafsson,et al.  Generation and reproductive phenotypes of mice lacking estrogen receptor beta. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[19]  R. McKay,et al.  The mammary microenvironment alters the differentiation repertoire of neural stem cells , 2008, Proceedings of the National Academy of Sciences.

[20]  Hua Tian,et al.  A paracrine requirement for hedgehog signalling in cancer , 2008, Nature.

[21]  T. Sakakura,et al.  Dual origin of mesenchymal tissues participating in mouse mammary gland embryogenesis. , 1982, Developmental biology.

[22]  P. Iannaccone,et al.  Emerging Roles for Hedgehog-Patched-Gli Signal Transduction in Reproduction1 , 2003, Biology of reproduction.

[23]  S. Robinson,et al.  TGF-beta 1-induced inhibition of mouse mammary ductal growth: developmental specificity and characterization. , 1989, Developmental biology.

[24]  D. Hanahan,et al.  Functions of Paracrine PDGF Signaling in the Proangiogenic Tumor Stroma Revealed by Pharmacological Targeting , 2008, PLoS medicine.

[25]  Z. Werb,et al.  Signaling through the stromal epidermal growth factor receptor is necessary for mammary ductal development. , 1999, Development.

[26]  C. Daniel,et al.  Direct action of 17 beta-estradiol on mouse mammary ducts analyzed by sustained release implants and steroid autoradiography. , 1987, Cancer research.

[27]  C. Rueden,et al.  Bmc Medicine Collagen Density Promotes Mammary Tumor Initiation and Progression , 2022 .

[28]  R. DePinho,et al.  Dissecting genetic requirements of human breast tumorigenesis in a tissue transgenic model of human breast cancer in mice , 2009, Proceedings of the National Academy of Sciences.

[29]  N. Boyd,et al.  Mammographic density and the risk and detection of breast cancer. , 2007, The New England journal of medicine.

[30]  Mina J. Bissell,et al.  Putting tumours in context , 2001, Nature Reviews Cancer.

[31]  R. Derynck,et al.  Evidence that transforming growth factor-β is a hormonally regulated negative growth factor in human breast cancer cells , 1987, Cell.

[32]  David L. Mack,et al.  Interaction with the mammary microenvironment redirects spermatogenic cell fate in vivo , 2007, Proceedings of the National Academy of Sciences.

[33]  Timothy Hunter,et al.  Molecular signatures suggest a major role for stromal cells in development of invasive breast cancer , 2009, Breast Cancer Research and Treatment.

[34]  N. Boyd,et al.  Mammographic density. Potential mechanisms of breast cancer risk associated with mammographic density: hypotheses based on epidemiological evidence , 2008, Breast Cancer Research.

[35]  Norman Boyd,et al.  The Association of Measured Breast Tissue Characteristics with Mammographic Density and Other Risk Factors for Breast Cancer , 2005, Cancer Epidemiology Biomarkers & Prevention.

[36]  T. Sakakura,et al.  Participation of two different mesenchymes in the developing mouse mammary gland: synthesis of basement membrane components by fat pad precursor cells. , 1985, Journal of embryology and experimental morphology.

[37]  L. Wakefield,et al.  Latent transforming growth factor-beta activation in mammary gland: regulation by ovarian hormones affects ductal and alveolar proliferation. , 2002, The American journal of pathology.

[38]  T. Sakakura,et al.  Mesenchyme-dependent morphogenesis and epithelium-specific cytodifferentiation in mouse mammary gland. , 1976, Science.

[39]  A. Kate Sasser,et al.  Mesenchymal Stem Cell Transition to Tumor-Associated Fibroblasts Contributes to Fibrovascular Network Expansion and Tumor Progression , 2009, PloS one.

[40]  C. Bucana,et al.  Targeting the expression of platelet-derived growth factor receptor by reactive stroma inhibits growth and metastasis of human colon carcinoma. , 2006, The American journal of pathology.

[41]  Rameen Beroukhim,et al.  Molecular characterization of the tumor microenvironment in breast cancer. , 2004, Cancer cell.

[42]  I. Haviv,et al.  Clonal mutations in the cancer-associated fibroblasts: the case against genetic coevolution. , 2009, Cancer research.

[43]  E. Cukierman.  A Visual-Quantitative Analysis of Fibroblastic Stromagenesis in Breast Cancer Progression , 2004, Journal of Mammary Gland Biology and Neoplasia.

[44]  C. Ruiz,et al.  Tenascin-W is a novel marker for activated tumor stroma in low-grade human breast cancer and influences cell behavior. , 2007, Cancer research.

[45]  Dennis C. Sgroi,et al.  Stromal Fibroblasts Present in Invasive Human Breast Carcinomas Promote Tumor Growth and Angiogenesis through Elevated SDF-1/CXCL12 Secretion , 2005, Cell.

[46]  J. Thiery,et al.  Role of FGF10/FGFR2b signaling during mammary gland development in the mouse embryo. , 2002, Development.

[47]  R. Weinberg,et al.  Systemic stromal effects of estrogen promote the growth of estrogen receptor-negative cancers. , 2007, Cancer research.

[48]  K. Schwertfeger.  Fibroblast growth factors in development and cancer: insights from the mammary and prostate glands. , 2009, Current drug targets.

[49]  P. Chambon,et al.  Paracrine signaling through the epithelial estrogen receptor α is required for proliferation and morphogenesis in the mammary gland , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[50]  A. Bellini,et al.  The role of the fibrocyte, a bone marrow-derived mesenchymal progenitor, in reactive and reparative fibroses , 2007, Laboratory Investigation.

[51]  J. Wolfe.  Breast patterns as an index of risk for developing breast cancer. , 1976, AJR. American journal of roentgenology.

[52]  P. Hein,et al.  Carcinoma-associated fibroblasts stimulate tumor progression of initiated human epithelium , 2000, Breast Cancer Research.

[53]  D. Sheppard,et al.  Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix , 2006, Proceedings of the National Academy of Sciences.

[54]  M. Stacey,et al.  Fibrocytes contribute to the myofibroblast population in wounded skin and originate from the bone marrow. , 2005, Experimental cell research.

[55]  F. Pépin,et al.  Stromal gene expression predicts clinical outcome in breast cancer , 2008, Nature Medicine.

[56]  M. Cazzaniga,et al.  Randomized dose-ranging trial of tamoxifen at low doses in hormone replacement therapy users. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[57]  F. Talamantes,et al.  Mammary phenotypic expression induced in epidermal cells by embryonic mammary mesenchyme. , 1995, Acta anatomica.

[58]  R. Langer,et al.  Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women: The Women's Health Initiative Randomized Trial , 2003 .

[59]  M. P. Walker,et al.  Mammary gland branching morphogenesis is diminished in mice with a deficiency of insulin-like growth factor-I (IGF-I), but not in mice with a liver-specific deletion of IGF-I. , 2004, Endocrinology.

[60]  K. Korach,et al.  Effect of Exogenous Epidermal-Like Growth Factors on Mammary Gland Development and Differentiation in the Estrogen Receptor-Alpha Knockout (ERKO) Mouse , 2003, Breast Cancer Research and Treatment.

[61]  Liang Xie,et al.  Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. , 2007, Cancer research.

[62]  R. Coffey,et al.  Transforming growth factor β regulation of cell proliferation , 1987, Journal of cellular physiology. Supplement.

[63]  R. Moll,et al.  CD34+ fibrocytes in invasive ductal carcinoma, ductal carcinoma in situ, and benign breast lesions , 2002, Virchows Archiv.

[64]  D. Proia,et al.  Reconstruction of human mammary tissues in a mouse model , 2006, Nature Protocols.

[65]  K. Korach,et al.  Mammary Gland Development and Tumorigenesis in Estrogen Receptor Knockout Mice , 1997, Journal of Mammary Gland Biology and Neoplasia.

[66]  David C. Lee,et al.  Targeted inactivation of the EGF and amphiregulin genes reveals distinct roles for EGF receptor ligands in mouse mammary gland development. , 1999, Development.

[67]  P. Kelly,et al.  Prolactin, growth hormone, and epidermal growth factor activate Stat5 in different compartments of mammary tissue and exert different and overlapping developmental effects. , 2001, Developmental biology.

[68]  J. Mesirov,et al.  Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells. , 2008, Cancer research.

[69]  S. Denmeade,et al.  Targeting the cancer stroma with a fibroblast activation protein-activated promelittin protoxin , 2009, Molecular Cancer Therapeutics.

[70]  Jun Yao,et al.  Distinct epigenetic changes in the stromal cells of breast cancers , 2005, Nature Genetics.

[71]  Michael C. Ostrowski,et al.  Genomic alterations in tumor stroma. , 2009, Cancer research.

[72]  T. Sakakura.  New aspects of stroma-parenchyma relations in mammary gland differentiation. , 1991, International review of cytology.

[73]  M. Barcellos-Hoff,et al.  Transforming growth factor-β in breast cancer: too much, too late , 2009, Breast Cancer Research.

[74]  N F Boyd,et al.  Growth factors and stromal matrix proteins associated with mammographic densities. , 2001, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[75]  R. Tarnuzzer,et al.  Estrogen accelerates cutaneous wound healing associated with an increase in TGF-β1 levels , 1997, Nature Medicine.

[76]  David Allard,et al.  Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer , 2009, Science.

[77]  W. Willett,et al.  Plasma insulin-like growth factor (IGF) I, IGF-binding protein 3, and mammographic density. , 2000, Cancer research.

[78]  N. Fusenig,et al.  Friends or foes — bipolar effects of the tumour stroma in cancer , 2004, Nature Reviews Cancer.

[79]  H. Dvorak.  Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. , 1986, The New England journal of medicine.

[80]  M. Bissell,et al.  Epithelial to mesenchymal transition in human breast cancer can provide a nonmalignant stroma. , 2003, The American journal of pathology.

[81]  D. Sharpe,et al.  17β-Estradiol regulates the secretion of TGF-β by cultured human dermal fibroblasts , 2008, Journal of biomaterials science. Polymer edition.

[82]  Brian Bierie,et al.  Tumour microenvironment: TGFβ: the molecular Jekyll and Hyde of cancer , 2006, Nature Reviews Cancer.

[83]  C M Rutter,et al.  Changes in breast density associated with initiation, discontinuation, and continuing use of hormone replacement therapy. , 2001, JAMA.

[84]  T. Sellers,et al.  Can genes for mammographic density inform cancer aetiology? , 2008, Nature Reviews Cancer.

[85]  A. Frost,et al.  Hedgehog Signaling in Mammary Gland Development and Breast Cancer , 2007, Journal of Mammary Gland Biology and Neoplasia.

[86]  R. Langer,et al.  Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. , 2003, JAMA.

[87]  B. Gusterson,et al.  Human breast development. , 2012, Seminars in cell & developmental biology.

[88]  Klaus Kratochwil,et al.  Regulation of Mammary Gland Development by Tissue Interaction , 2004, Journal of Mammary Gland Biology and Neoplasia.

[89]  James A. Clark,et al.  Mammary Gland Development in Adult Mice Requires Epithelial and Stromal Estrogen Receptor α. , 2002, Endocrinology.

[90]  M J Bissell,et al.  Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction. , 1996, Physiological reviews.

[91]  M. Bissell,et al.  The origin of the myofibroblasts in breast cancer. Recapitulation of tumor environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth muscle cells. , 1995, The Journal of clinical investigation.

[92]  L. Ellis,et al.  VEGF-targeted therapy: mechanisms of anti-tumour activity , 2008, Nature Reviews Cancer.

[93]  H. Bern,et al.  Development of mammary tumors from hyperplastic alveolar nodules transplanted into gland-free mammary fat pads of female C3H mice. , 1959, Cancer research.

[94]  Stephen W Duffy,et al.  Tamoxifen and breast density in women at increased risk of breast cancer. , 2004, Journal of the National Cancer Institute.

[95]  K. Heider,et al.  Effective Immunoconjugate Therapy in Cancer Models Targeting a Serine Protease of Tumor Fibroblasts , 2008, Clinical Cancer Research.

[96]  M. Skobe,et al.  Tumorigenic conversion of immortal human keratinocytes through stromal cell activation. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[97]  S. Coleman,et al.  Ductal morphogenesis in the mouse mammary gland: evidence supporting a role for epidermal growth factor. , 1988, Developmental biology.

[98]  J. Gustafsson,et al.  Estrogen receptors α and β in the rodent mammary gland , 2000, Breast Cancer Research.

[99]  R. Weinberg,et al.  Reconstruction of functionally normal and malignant human breast tissues in mice. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[100]  B. Hogan,et al.  Inhibition of mammary duct development but not alveolar outgrowth during pregnancy in transgenic mice expressing active TGF-beta 1. , 1993, Genes & development.

[101]  K. Deome,et al.  Growth of Mouse Mammary Glands in vivo after Monolayer Culture , 1965, Science.

[102]  D. Botstein,et al.  The transcriptional program in the response of human fibroblasts to serum. , 1999, Science.