Reconstruction of functionally normal and malignant human breast tissues in mice

Kuperwasser, Charlotte; Chavarria, Tony E.; Wu, Min; Magrane, Greg; Gray, Joe W.; Carey, Loucinda; Richardson, Andrea; Weinberg, Robert A.

doi:10.1073/pnas.0401064101

Cited by 697 publications

(663 citation statements)

References 28 publications

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“…The importance of locally produced rather than systemic IGF1 is also supported by the observation that mammary branching proceeds normally in mice with a liver-specific IGF1 deletion that results in a 75% decrease in circulating IGF1 levels without affecting mammary-specific IGF1 production [15]. On the other hand, mammary branching is impeded in global IGF1 knockout mice lacking both systemic and local IGF1 production.…”

Section: What Cues Act Upstream Of the Adam17-areg-egfr Axis?mentioning

confidence: 90%

“…And, as is true in mice, stromal factors are also apt to influence human breast development. Indeed, human breast epithelial cells will only form functional glandular structures if they are transplanted to 'humanized' mouse mammary fat pads that contain human breast fibroblasts [15] or if they are transplanted within collagen matrix gels that also contain normal human or mouse mammary fibroblasts [16]. Thus, stromal celland matrix-derived signals appear to play a critical role in mammary ductal development, which raises obvious questions concerning what stromal factors are involved and how they influence the developing epithelium.…”

Section: Introductionmentioning

confidence: 99%

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The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer

Sternlicht

Sunnarborg

2008

J Mammary Gland Biol Neoplasia

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In order to fulfill its function of producing and delivering sufficient milk to newborn mammalian offspring, the mammary gland first has to form an extensive ductal network. As in all phases of mammary development, hormonal cues elicit local intra-and inter-cellular signaling cascades that regulate ductal growth and differentiation. Among other things, ductal development requires the epidermal growth factor receptor (EGFR), its ligand amphiregulin (AREG), and the transmembrane metalloproteinase AD-AM17, which can cleave and release AREG from the cell surface so that it may interact with its receptor. Tissue recombination and transplantation studies demonstrate that EGFR phosphorylation and ductal development proceed only when ADAM17 and AREG are expressed on mammary epithelial cells and EGFR is present on stromal cells, and that local administration of soluble AREG can rescue the development of ADAM17-deficient transplants. Thus proper mammary morphogenesis requires the ADAM17-mediated release of AREG from ductal epithelial cells, the subsequent activation of EGFR on stromal cells, and EGFR-dependent stromal responses that in return elicit a new set of epithelial responses, all culminating in the formation of a fully functional ductal tree. This, however, raises new issues concerning what may act upstream, downstream or in parallel with the ADAM17-AREG-EGFR axis, how it may become hijacked or corrupted during the onset and evolution of cancer, and how such ill effects may be confronted.

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Section: What Cues Act Upstream Of the Adam17-areg-egfr Axis?mentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer

Sternlicht

Sunnarborg

2008

J Mammary Gland Biol Neoplasia

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“…Many functional studies have demonstrated the importance of fibroblasts in cancer initiation 1 , progression [2][3][4] and metastases 5 . In animal models of prostate and breast cancers, oncogene-modified epithelial cells became malignant or showed enhanced growth when coinoculated with fibroblasts that were either oncogene induced 6 or derived from fresh human carcinoma tissues 2,3 (that is, CAFs).…”

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confidence: 99%

No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas

et al. 2008

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There is increasing evidence showing that the stromal cells surrounding cancer epithelial cells, rather than being passive bystanders, might have a role in modifying tumor outgrowth. The molecular basis of this aspect of carcinoma etiology is controversial. Some studies have reported a high frequency of genetic aberrations in carcinoma-associated fibroblasts (CAFs), whereas other studies have reported very low or zero mutation rates. Resolution of this contentious area is of critical importance in terms of understanding both the basic biology of cancer as well as the potential clinical implications of CAF somatic alterations. We undertook genome-wide copy number and loss of heterozygosity (LOH) analysis of CAFs derived from breast and ovarian carcinomas using a 500K SNP array platform. Our data show conclusively that LOH and copy number alterations are extremely rare in CAFs and cannot be the basis of the carcinomapromoting phenotypes of breast and ovarian CAFs. © 2008 Nature Publishing GroupCorrespondence should be addressed to I.G.C. ian.campbell@petermac.org. AUTHOR CONTRIBUTIONS I.G.C., I.H. and W.Q. designed the study and wrote the paper. W.Q. undertook the bulk of the experimental work including tissue microdissection, SNP genotyping and microsatellite analysis. K.P. provided cell lines, academic support and assisted in manuscript preparation. A.S., E.R.T., M.R. and K.L.G. assisted in SNP genotyping. However, not all studies have identified genetic alterations in CAFs; for example, one study did not find any clonally selected somatic genetic alterations in CAFs separated from fresh breast cancer biopsies using array comparative genomic hybridization (CGH) and SNP array analysis 17 , although these CAFs were epigenetically distinct from those from normal breast tissue, as demonstrated by subsequent genome-wide DNA methylation studies 18 .The evidence for somatic genetic alterations as important mediators of the CAF phenotype is controversial and conflicting. We hypothesized that the contradictory data may in part be a reflection of inherent technical limitations of the various methodologies used. Therefore, we took advantage of innovative SNP array-based technologies 19 to investigate in detail the genomic integrity of CAFs microdissected from fresh frozen primary human ovarian and breast cancers as well as short-term cultures of primary breast CAFs.We assessed the sensitivity of the Affymetrix 500K SNP array platform to detect copy number and LOH in the context of normal DNA contamination in a mixing experiment using tumor epithelial cell DNA from a microdissected primary ovarian cancer that was mixed with various ratios of matched normal DNA. This tumor harbors a complex copy number profile on chromosome 17, including regions of high level copy number gain and regions of LOH with and without associated copy number loss. As shown in Supplementary Figure 1a online, the single copy number gain was clearly visible at 70% tumor DNA, and the high level gain was still discernible at 25% tumor DNA. LOH w...

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“…This experiment suggests that non-cell autonomous factors may play an important role in breast cancer etiology. Indeed, recent evidence that an altered stromal environment can enhance mammary tumor formation supports this hypothesis (Kuperwasser et al 2004).…”

Section: Using Defined Genetic Elements To Model Specific Cancer Typesmentioning

confidence: 93%

Immortalized cells as experimental models to study cancer

Boehm

Hahn

2004

Cytotechnology

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The development of cancer is a multi-step process in which normal cells sustain a series of genetic alterations that together program the malignant phenotype. Much of our knowledge of cancer biology results from the detailed study of specimens and cell lines derived from patient tumors. While these approaches continue to yield critical information regarding the identity, number, and types of alterations found in human tumors, further progress in understanding the molecular basis of malignant transformation depends upon the generation and use of increasingly sophisticated experimental models of cancer. Over the past several years, the recognition that telomeres and telomerase play essential roles in regulating cell lifespan now permits the development of new models of human cancer. Here we review recent progress in the use of immortalized human cells as a foundation for understanding the molecular basis of cancer.Abbreviations: ALT -alternative lengthening of telomeres; HEK -human embryonic kidney; HMEChuman mammary epithelial cell; HPV -human papillomavirus; hTERT -human telomerase reverse transcriptase; LT -SV40 Large T antigen; PD -population doubling; PP2A -protein phosphatase 2A; RalGEF -Ral guanine nucleotide exchange factor; RAS -activated H-Ras allele; shRNA -short hairpin RNA; ST -SV40 small t antigen; TRF -telomere restriction fragment.

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Reconstruction of functionally normal and malignant human breast tissues in mice

Cited by 697 publications

References 28 publications

The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer

The ADAM17–amphiregulin–EGFR Axis in Mammary Development and Cancer

No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas

Immortalized cells as experimental models to study cancer

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