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Mammary carcinoma behavior is programmed in the precancer stem cell.

Damonte P, Hodgson JG, Chen JQ, Young LJ, Cardiff RD, Borowsky AD - Breast Cancer Res. (2008)

Bottom Line: No changes are associated with progression, although spontaneous focal amplifications and deletions were detected occasionally.Telomerase activity is increased in both the MINO and the derived tumors when compared with normal mouse mammary gland.Within the context of this model, these cells have programmed potential for latency and metastasis that does not appear to require sequential genetic 'hits' for transformation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Center for Comparative Medicine, UC Davis, County Road 98 and Hutchison Drive, Davis, California 95616, USA.

ABSTRACT

Introduction: The 'MINO' (mammary intraepithelial neoplasia outgrowth) mouse model of ductal carcinoma in situ (DCIS) consists of six lines with distinct morphologic phenotypes and behavior, each meeting experimentally defined criteria for 'precancer'. Specifically, these lines grow orthotopically in cleared mammary fat pads and consistently progress to an invasive phenotype that is capable of ectopic growth. Transition to carcinoma has a consistent latency for each line, and three of the lines also exhibit pulmonary metastatic potential.

Methods: Gland cleared orthotopic transplanted precancer MINO tissues were analyzed by bacterial artifical chromosome and oligo array comparative genomic hybridization, microsatellite PCR, and telomerase repeat amplification assay. MINO cells were dissociated and cultured in three dimensional culture and transplanted in syngeneic gland cleared mammary fat pads.

Results: Comparative genomic hybridization shows that the precancer and invasive tumors are genetically stable, with low level changes including whole chromosome gains in some lines. No changes are associated with progression, although spontaneous focal amplifications and deletions were detected occasionally. Microsatellite analysis shows a low frequency of alterations that are predominantly permanent within a MINO line. Telomerase activity is increased in both the MINO and the derived tumors when compared with normal mouse mammary gland. Dissociation of the precancer lesion cells and three dimensional 'spheroid' culture of single cells reveals a bipotential for myoepithelial and luminal differentiation and the formation of unique three-dimensional 'MINOspheres'. These MINOspheres exhibit features that are intermediate between spheroids that are derived from normal and carcinoma cells. Transplantation of a single cell derived MINOsphere recapitulates the outgrowth of the precancer morphology and progression to carcinoma.

Conclusion: These data establish a precancer 'stem' cell that is capable of self-renewal and multilineage differentiation as the origin of invasive cancer. Within the context of this model, these cells have programmed potential for latency and metastasis that does not appear to require sequential genetic 'hits' for transformation.

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Conceptual models of breast cancer progression. (a) Sequential acquisition of molecular alterations with selection of advantageous 'hits' and corresponding morphologic progression (modified from Burstein and coworkers [4]). Individual 'hits' are depicted with small 'lightening bolts'. (b) Hyperplasia results in shortening telomeres, rapidly increasing genetic instability during 'telomere crisis', and relative stability after telomerase reactivation (modified from Chin and coworkers [15]). Individual cells reactivating telomerase and with a 'fit' genetic profile give rise to the carcinoma in situ (DCIS) and then the invasive carcinoma. (c) Genetically stable precancer stem cells are initiated via oncogene activation with divergent behavior programmed via epigenetic encoding and possible but not required genetic content changes. Intermediate morphologic and molecular events are not required for progression. These cells give rise to the DCIS and have an innate latency to invasive carcinoma and an innate metastatic potential.
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Figure 5: Conceptual models of breast cancer progression. (a) Sequential acquisition of molecular alterations with selection of advantageous 'hits' and corresponding morphologic progression (modified from Burstein and coworkers [4]). Individual 'hits' are depicted with small 'lightening bolts'. (b) Hyperplasia results in shortening telomeres, rapidly increasing genetic instability during 'telomere crisis', and relative stability after telomerase reactivation (modified from Chin and coworkers [15]). Individual cells reactivating telomerase and with a 'fit' genetic profile give rise to the carcinoma in situ (DCIS) and then the invasive carcinoma. (c) Genetically stable precancer stem cells are initiated via oncogene activation with divergent behavior programmed via epigenetic encoding and possible but not required genetic content changes. Intermediate morphologic and molecular events are not required for progression. These cells give rise to the DCIS and have an innate latency to invasive carcinoma and an innate metastatic potential.

Mentions: The model of breast cancer progression via sequential acquisition of selectively advantageous molecular alterations with morphologically recognizable phenotypes is a convenient conceptual framework (Figure 5a). However, alternative models are possible. Progression from one lesion to the next cannot be experimentally tested in human populations, although several associations are clear. DCIS is associated with invasive cancer in close anatomic proximity. However, progression of DCIS through sequential grades and progression of invasive cancer from low to high grade or from estrogen receptor positive to negative is not common in patient pathology studies. Purported precursor lesions of hyperplasia and atypical hyperplasia are not known to carry higher risks for cancer at the site of the lesion. Instead, they are markers of risk throughout the breast. Although there is molecular evidence of clonal relationship between some of these lesions and associated cancer, the same analysis shows clonality with 'normal' mammary epithelium. Finally, the specific 'hits' that are responsible for the transition from DCIS to invasive cancer remain elusive despite extensive study.


Mammary carcinoma behavior is programmed in the precancer stem cell.

Damonte P, Hodgson JG, Chen JQ, Young LJ, Cardiff RD, Borowsky AD - Breast Cancer Res. (2008)

Conceptual models of breast cancer progression. (a) Sequential acquisition of molecular alterations with selection of advantageous 'hits' and corresponding morphologic progression (modified from Burstein and coworkers [4]). Individual 'hits' are depicted with small 'lightening bolts'. (b) Hyperplasia results in shortening telomeres, rapidly increasing genetic instability during 'telomere crisis', and relative stability after telomerase reactivation (modified from Chin and coworkers [15]). Individual cells reactivating telomerase and with a 'fit' genetic profile give rise to the carcinoma in situ (DCIS) and then the invasive carcinoma. (c) Genetically stable precancer stem cells are initiated via oncogene activation with divergent behavior programmed via epigenetic encoding and possible but not required genetic content changes. Intermediate morphologic and molecular events are not required for progression. These cells give rise to the DCIS and have an innate latency to invasive carcinoma and an innate metastatic potential.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2481504&req=5

Figure 5: Conceptual models of breast cancer progression. (a) Sequential acquisition of molecular alterations with selection of advantageous 'hits' and corresponding morphologic progression (modified from Burstein and coworkers [4]). Individual 'hits' are depicted with small 'lightening bolts'. (b) Hyperplasia results in shortening telomeres, rapidly increasing genetic instability during 'telomere crisis', and relative stability after telomerase reactivation (modified from Chin and coworkers [15]). Individual cells reactivating telomerase and with a 'fit' genetic profile give rise to the carcinoma in situ (DCIS) and then the invasive carcinoma. (c) Genetically stable precancer stem cells are initiated via oncogene activation with divergent behavior programmed via epigenetic encoding and possible but not required genetic content changes. Intermediate morphologic and molecular events are not required for progression. These cells give rise to the DCIS and have an innate latency to invasive carcinoma and an innate metastatic potential.
Mentions: The model of breast cancer progression via sequential acquisition of selectively advantageous molecular alterations with morphologically recognizable phenotypes is a convenient conceptual framework (Figure 5a). However, alternative models are possible. Progression from one lesion to the next cannot be experimentally tested in human populations, although several associations are clear. DCIS is associated with invasive cancer in close anatomic proximity. However, progression of DCIS through sequential grades and progression of invasive cancer from low to high grade or from estrogen receptor positive to negative is not common in patient pathology studies. Purported precursor lesions of hyperplasia and atypical hyperplasia are not known to carry higher risks for cancer at the site of the lesion. Instead, they are markers of risk throughout the breast. Although there is molecular evidence of clonal relationship between some of these lesions and associated cancer, the same analysis shows clonality with 'normal' mammary epithelium. Finally, the specific 'hits' that are responsible for the transition from DCIS to invasive cancer remain elusive despite extensive study.

Bottom Line: No changes are associated with progression, although spontaneous focal amplifications and deletions were detected occasionally.Telomerase activity is increased in both the MINO and the derived tumors when compared with normal mouse mammary gland.Within the context of this model, these cells have programmed potential for latency and metastasis that does not appear to require sequential genetic 'hits' for transformation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Center for Comparative Medicine, UC Davis, County Road 98 and Hutchison Drive, Davis, California 95616, USA.

ABSTRACT

Introduction: The 'MINO' (mammary intraepithelial neoplasia outgrowth) mouse model of ductal carcinoma in situ (DCIS) consists of six lines with distinct morphologic phenotypes and behavior, each meeting experimentally defined criteria for 'precancer'. Specifically, these lines grow orthotopically in cleared mammary fat pads and consistently progress to an invasive phenotype that is capable of ectopic growth. Transition to carcinoma has a consistent latency for each line, and three of the lines also exhibit pulmonary metastatic potential.

Methods: Gland cleared orthotopic transplanted precancer MINO tissues were analyzed by bacterial artifical chromosome and oligo array comparative genomic hybridization, microsatellite PCR, and telomerase repeat amplification assay. MINO cells were dissociated and cultured in three dimensional culture and transplanted in syngeneic gland cleared mammary fat pads.

Results: Comparative genomic hybridization shows that the precancer and invasive tumors are genetically stable, with low level changes including whole chromosome gains in some lines. No changes are associated with progression, although spontaneous focal amplifications and deletions were detected occasionally. Microsatellite analysis shows a low frequency of alterations that are predominantly permanent within a MINO line. Telomerase activity is increased in both the MINO and the derived tumors when compared with normal mouse mammary gland. Dissociation of the precancer lesion cells and three dimensional 'spheroid' culture of single cells reveals a bipotential for myoepithelial and luminal differentiation and the formation of unique three-dimensional 'MINOspheres'. These MINOspheres exhibit features that are intermediate between spheroids that are derived from normal and carcinoma cells. Transplantation of a single cell derived MINOsphere recapitulates the outgrowth of the precancer morphology and progression to carcinoma.

Conclusion: These data establish a precancer 'stem' cell that is capable of self-renewal and multilineage differentiation as the origin of invasive cancer. Within the context of this model, these cells have programmed potential for latency and metastasis that does not appear to require sequential genetic 'hits' for transformation.

Show MeSH
Related in: MedlinePlus