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Loss of cyclin D1 in concert with deregulated estrogen receptor alpha expression induces DNA damage response activation and interrupts mammary gland morphogenesis.

ABSTRACT: We have previously shown that increased and deregulated estrogen receptor alpha expression in the mammary gland leads to the development of proliferative disease and cancer. To address the importance of cyclin D1 in ERalpha-mediated mammary tumorigenesis, we crossed ERalpha-overexpressing mice with cyclin D1 knockout mice. Mammary gland morphogenesis was completely interrupted in the ERalpha-overexpressing cyclin D1-deficient triple transgenic mice. In addition to a highly significant reduction in mammary epithelial cell proliferation, cyclin E was upregulated resulting in DNA damage checkpoint activation and apoptosis. This imbalance between proliferative and apoptotic rates in conjunction with remarkable structural defects and cellular disorganization in the terminal end buds interrupted ductal morphogenesis. Interestingly, the structure of the mammary fat pad was fundamentally altered by the consequences of overexpressing ERalpha in the epithelial cells in the absence of cyclin D1 illustrating how alterations in the epithelial compartment can impact surrounding stromal composition. Transplantation of embryonic ERalpha-overexpressing and cyclin D1-deficient mammary epithelium into the cleared fat pad of wild-type mice did not rescue the aberrant mammary gland phenotype indicating that it was intrinsic to the mammary epithelial cells. In conclusion, although cyclin D1 is not essential for proliferation of normal mammary epithelial cells, ERalpha-overexpressing cells are absolutely dependent on cyclin D1 for proliferation. This differential requirement for cyclin D1 in normal vs abnormal mammary epithelial cells supports the application of cyclin D1 inhibitors as therapeutic interventions in ERalpha-overexpressing breast cancers.

SUBMITTER: Frech MS

PROVIDER: S-EPMC7007637 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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Loss of cyclin D1 in concert with deregulated estrogen receptor alpha expression induces DNA damage response activation and interrupts mammary gland morphogenesis.

Frech M S MS Torre K M KM Robinson G W GW Furth P A PA

Oncogene 20071210 22

We have previously shown that increased and deregulated estrogen receptor alpha expression in the mammary gland leads to the development of proliferative disease and cancer. To address the importance of cyclin D1 in ERalpha-mediated mammary tumorigenesis, we crossed ERalpha-overexpressing mice with cyclin D1 knockout mice. Mammary gland morphogenesis was completely interrupted in the ERalpha-overexpressing cyclin D1-deficient triple transgenic mice. In addition to a highly significant reduction ...[more]

PMID: 18071314

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Project description:BACKGROUND: The Tientsin Albino 2 (TA2) mouse is an inbred strain originating from the Kunming strain. It has a high incidence of spontaneous breast cancer without the need for external inducers or carcinogens. Until now, the mechanism of carcinogenesis has remained unclear. In this study, we investigate differential gene expression, especially the expression of decorin, EGFR and cyclin D1, during mammary gland epithelial cell carcinogenesis in TA2 mice. METHODS: Gene expression profiles of spontaneous breast cancer and matched normal mammary gland tissues in TA2 mice were ascertained using an Affymetrix Mouse 430 2.0 array. Twelve mammary tissue samples from five month-old female TA2 mice (Group A), as well as 28 samples from mammary (Group B) and cancer tissues (Group C) of spontaneous breast cancer-bearing TA2 mice, were subsequently used to detect the expression of decorin, EGFR and cyclin D1 by real-time PCR and immunohistochemical methods. RESULTS: Several imprinted genes, oncogenes and tumor suppressor genes were differentially expressed between normal mammary gland tissues and breast cancer tissues of TA2 mice. The imprinted gene decorin and the oncogene EGFR were down-regulated in tumor tissues, while the oncogene cyclin D1 was up-regulated. Immunohistochemistry showed that samples in Group A showed high decorin expression more frequently than those in Group B (P < 0.05). More tissue samples in Group B than Group A were positive for nuclear EGFR, and tissue samples in Group B more frequently showed high nuclear EGFR expression than those in Group A or Group C (P < 0.05). The labeling index for cyclin D1 in Group C was significantly higher than in Group B. Mammary tissues of Group A expressed the highest level of decorin mRNA (P < 0.05), and mammary tissues of Group B expressed the highest level of EGFR mRNA (P < 0.05), while cancer tissues expressed the highest level of cyclin D1 mRNA (P < 0.05). CONCLUSIONS: The expression of decorin, EGFR and cyclin D1 in mammary epithelial cells changes with increasing age. The abnormal expression of them may partly contribute to the genesis of spontaneous breast cancer in TA2 mice.

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Loss of cyclin D1 in concert with deregulated estrogen receptor alpha expression induces DNA damage response activation and interrupts mammary gland morphogenesis.

Publications

Loss of cyclin D1 in concert with deregulated estrogen receptor alpha expression induces DNA damage response activation and interrupts mammary gland morphogenesis.

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