I have found that mouse mammary tumors demonstrate a remarkable preference for growth in their natural anatomic site, the mammary fatpad. Furthermore, mouse mammary tumors were found to metastasize more readily from the mammary fatpad than from subcutaneous sites. I have shown that immunological mechanisms do not adequately explain these observed site effects on tumor growth and metastasis and have focused on intraepithelial and stromal-epithelial cellular interactions as alternative mechanisms. Interactive homeostatic mechanisms occur between cells from the time of blastlal formation. These regulatory processes are usually able to maintain tissue integrity throughout life and can be regarded as mechanisms of """"""""non-immune surveillance"""""""" against neoplasia. In the mouse, normal mammary gland tissue interactions can be demonstrated as early as in the 11 day (in utero) fetal mammary bud, in the virgin female, during pregnancy/lactation related glandular remodeling, between mammary epithelium and preneoplastic mammary tissues, and, as I have shown, between normal mammary gland tissues and malignant mammary tissues. Manipulation of tissue interactions could lead to new therapeutic strategies against cancer growth and progression. I have developed mammary tumor lines with drug resistance markers and have utilized these to study metabolic cooperation between mammary tissues. I have adapted the three-dimensional culture system in collagen gel to study tissue interactions in vitro, and I have begun to utilize embryonic tissues as a defined source of functional mammary mesechyme to study epithelial-mesenchymal interactions with mammary tumor cells. These new tools will aid my continuing investigations of mammary tumors growing in their natural anatomic site to determine both the mechanisms of site preference and their consequences. The study of mechanism will continue to focus on cellular interactions within the mammary gland fatpad. The studies of the consequences will focus on the affect of mammary gland tissue interactions on neoplastic progression. My experimental approaches are based on the principles that cell shape, tissue architecture, the extracellular matrix, and both stromal-epithelial and intraepithelial interactions may all play significant roles in the normal growth and development of the mammary gland.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA028366-07
Application #
3168096
Study Section
Pathology B Study Section (PTHB)
Project Start
1980-06-01
Project End
1989-06-30
Budget Start
1986-07-01
Budget End
1987-06-30
Support Year
7
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Barbara Ann Karmanos Cancer Institute
Department
Type
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48201
Santner, S J; Dawson, P J; Tait, L et al. (2001) Malignant MCF10CA1 cell lines derived from premalignant human breast epithelial MCF10AT cells. Breast Cancer Res Treat 65:101-10
Miller, F R (2000) Xenograft models of premalignant breast disease. J Mammary Gland Biol Neoplasia 5:379-91
Strickland, L B; Dawson, P J; Santner, S J et al. (2000) Progression of premalignant MCF10AT generates heterogeneous malignant variants with characteristic histologic types and immunohistochemical markers. Breast Cancer Res Treat 64:235-40
Wang, B; Miller, F R (2000) Tyrosine phosphorylation of an erbB-2 related p90 protein induced by estrogen in human breast epithelial cells. Int J Oncol 16:1035-42
Miller, F R; Barnbabas, N; Liu, X et al. (1999) Differential display, subtractive hybridization, and application of methodology to search for point mutations to identify genetic defects responsible for progression in MCF10AT model of human breast disease. Electrophoresis 20:256-60
Iravani, S; Mora, L; Miller, F R et al. (1998) Altered expression of c-erbB-2, DF3, b72.3, p53 and Ki-67 with progression and differentiation to two distinct histologic types of invasive carcinoma in the MCF10AT human xenograft model of proliferative breast disease. Int J Oncol 12:369-75
Wang, B; Soule, H D; Miller, F R (1997) Transforming and oncogenic potential of activated c-Ha-ras in three immortalized human breast epithelial cell lines. Anticancer Res 17:4387-94
Wolman, S R; Heppner, G H; Wolman, E (1997) New directions in breast cancer research. FASEB J 11:535-43
Miller, F R (1996) Models of progression spanning preneoplasia and metastasis: the human MCF10AneoT.TGn series and a panel of mouse mammary tumor subpopulations. Cancer Treat Res 83:243-63
Miller, F R; Pauley, R J; Wang, B (1996) Activated c-Ha-ras is not sufficient to produce the preneoplastic phenotype of human breast cell line MCF10AT. Anticancer Res 16:1765-9

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