Activated expression of growth regulating peptides is a hallmark of neoplasia. The conspicuous induction of transforming growth factor-alpha (TCFalpha) in a wide array of human and animal tumors, as well as in transformed cell lines, is a case in point. A member of the EGF receptor ligand family, TGFalpha is a potent mitogen for epithelial and mesenchymal cells. It also regulates cell differentiation and migration, and it has been implicated in angiogenesis, wound healing and liver regeneration. To explore the pathological consequences of activated TGFalpha expression we created lines of transgenic mice that overexpress the growth factor in multiple tissues. A significant consequence was the development of breast cancer with high incidence in postlactational females. Targeted expression of TGFalpha in the lactating mammary gland under the control of the whey acidic protein (WAP) promoter produced transplantable carcinomas, one of which metastasized to lung. In multiparous females, focal tumors were found in association with large number os hyperplastic alveolar (HANs) the origin of which is suggested by our observation that TGFalpha blocked, or at least partially inhibited, the normal destruction of mammary glands at the end of lactation (involution). IN light of these various results, we hypothesize that not-regressed glands constitute preneoplastic lesions. Cells in a fraction of these eventually form tumors as a result of additional genetic events. We propose to further examine the mechanisms by which TGFalpha induces breast cancer in these unique models.
Our Specific Aims are to: (1) characterize the molecular characterize the molecular phenotypes of breast tumors induced by deregulated expression of TGFalpha; 2) investigate the mechanism(s) by which expression the WAP- TGFalpha transgene initiates the development of breast cancer; and 3) explore the possibility that TGFalpha transgenic mice provide a model with which to study neoplastic progression in breast.
In Aim I, we will correlate patterns and levels of expression of the different transgenes, and compare these results with various characteristics of the resulting tumors, focussing in part on how neoplastic induction by a polypeptide growth factor influences steroid hormone responsiveness of resulting tumors. Additionally, we will look for amplification and/or activated expression of particular candidate genes (e.g. EGF-R and new), and we will develop new transgenic models for other members of the ligand/receptor signalling family, In Aim II, we will further explore effects of TGFalpha on the development on the development and regression of mammary glands with a particular focus on the possibility that it blocks the normal apoptotic events. We will also examine the activity of a non-cleavable form of proTGFalpha.
In Aim III, we will further characterize the TGFalpha-induced HANs to determine whether they provide a model of neoplastic progression, and we will utilize a retroviral tagging approach to identify genes that might cooperate with TGFalpha breast tumorigenesis.
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