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      From The Cover: Reconstruction of functionally normal and malignant human breast tissues in mice

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          Abstract

          The study of normal breast epithelial morphogenesis and carcinogenesis in vivo has largely used rodent models. Efforts at studying mammary morphogenesis and cancer with xenotransplanted human epithelial cells have failed to recapitulate the full extent of development seen in the human breast. We have developed an orthotopic xenograft model in which both the stromal and epithelial components of the reconstructed mammary gland are of human origin. Genetic modification of human stromal cells before the implantation of ostensibly normal human mammary epithelial cells resulted in the outgrowth of benign and malignant lesions. This experimental model allows for studies of human epithelial morphogenesis and differentiation in vivo and underscores the critical role of heterotypic interactions in human breast development and carcinogenesis.

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          Most cited references19

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          Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells.

          A number of genetic mutations have been identified in human breast cancers, yet the specific combinations of mutations required in concert to form breast carcinoma cells remain unknown. One approach to identifying the genetic and biochemical alterations required for this process involves the transformation of primary human mammary epithelial cells (HMECs) to carcinoma cells through the introduction of specific genes. Here we show that introduction of three genes encoding the SV40 large-T antigen, the telomerase catalytic subunit, and an H-Ras oncoprotein into primary HMECs results in cells that form tumors when transplanted subcutaneously or into the mammary glands of immunocompromised mice. The tumorigenicity of these transformed cells was dependent on the level of ras oncogene expression. Interestingly, transformation of HMECs but not two other human cell types was associated with amplifications of the c-myc oncogene, which occurred during the in vitro growth of the cells. Tumors derived from the transformed HMECs were poorly differentiated carcinomas that infiltrated through adjacent tissue. When these cells were injected subcutaneously, tumors formed in only half of the injections and with an average latency of 7.5 weeks. Mixing the epithelial tumor cells with Matrigel or primary human mammary fibroblasts substantially increased the efficiency of tumor formation and decreased the latency of tumor formation, demonstrating a significant influence of the stromal microenvironment on tumorigenicity. Thus, these observations establish an experimental system for elucidating both the genetic and cell biological requirements for the development of breast cancer.
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            Breast cancer and atypia among young and middle-aged women: a study of 110 medicolegal autopsies.

            In 110 consecutive, medicolegal autopsies of young and middle-aged women (range 20-54 years) the breasts were examined by an extensive histopathologic method and by correlative specimen radiography. Malignancy was found in 22 women (20%) of which only one was known to have had clinical invasive breast cancer (IBC). At autopsy 2 women had IBC (2%), the remaining in situ carcinoma (in situ BC) of microfocal type (18%), i.e. 15 (14%) intraductal carcinomas (DCIS), 4 (3%) lobular carcinoma in situ (LCIS) and one (1%) both DCIS and LCIS. Forty-five per cent of the women with malignancy had multicentric and 41% had bilateral lesions. Forty-five per cent of all histologically confirmed malignant lesions were identified by specimen radiography. Adenosis, benign epithelial hyperplasia, papilloma and duct ectasia were positively associated with malignancy. In addition malignancy was significantly more frequent among women aged more than 40 years, with late age at first full-term pregnancy, with alcohol abuse and with steatosis or cirrhosis of the liver. The results suggest that clinically occult in situ BC are frequent in young and middle-aged women. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7
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              Estrogen receptor-positive proliferating cells in the normal and precancerous breast.

              Recently it has been shown that epithelial cell expression of the estrogen receptor (ER) and that of the proliferation-associated marker Ki-67 are almost mutually exclusive in the normal premenopausal human breast but that coexpression frequently occurs in estrogen receptor-positive (ER+) breast cancers. This coexpression may indicate disordered expression of ER in the cell cycle or failure to suppress division of ER+ cells and could be important in neoplastic transformation. The purpose of this study was to determine whether in situ proliferations known to be associated with different levels of risk for developing breast cancer contain these coexpressing cells and, if so, the stage at which they occur. We found that ER+ proliferating cells were rare in premenopausal lobules but increased with age in the normal breast. There was no difference in nonlesional tissue between cancerous and noncancerous breasts. The percentage of dual-expressing cells was significantly increased, however, in all of the in situ proliferations and correlated positively with the level of risk of developing breast cancer. We suggest that development of at least some human breast cancers is associated with increasing failure to down-regulate ER as cells enter the cycle or to suppress division of ER+ cells. The mechanism may involve the loss of a tumor suppressor gene.
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                Author and article information

                Journal
                Proceedings of the National Academy of Sciences
                Proceedings of the National Academy of Sciences
                Proceedings of the National Academy of Sciences
                0027-8424
                1091-6490
                April 06 2004
                April 06 2004
                March 29 2004
                April 06 2004
                : 101
                : 14
                : 4966-4971
                Article
                10.1073/pnas.0401064101
                387357
                15051869
                65f0149f-e757-4126-85e9-6fbaf57f7400
                © 2004
                History

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