Breast cancer is the leading cause of death in women in the United States and its incidence has rapidly increased over the past decade. This Program Project focuses on the biologic mechanisms whereby hormones control cellular proliferation, modulate genotypic and phenotypic cellular changes, and influence tumor invasiveness and metastasis. Several innovative new hypotheses arising from recent results in several of our laboratories will be tested in the studies proposed. To highlight some of these, we propose that constitutive polyamine synthesis may initiate an aggressive tumor phenotype; that insulin-like growth factor binding proteins may modulate tumor cell proliferation; that variant progesterone receptors may exert negative effects on progestin action; that neutrophils may serve to create holes in basement membranes allowing tumor cells to penetrate and invade tissues; and that tumor cells may develop enhanced estradiol sensitivity upon estrogen deprivation. The overall goals of the Program Project are to examine the mechanisms which modify the mitotic, cell proliferative, and metastatic behavior of breast cancer cells growing in vitro in liquid culture, in vivo in animal systems and spontaneously in patients. Identification of these mechanisms should allow targeting of therapy to specific key processes. The strengths and expertise of the investigators participating in this Program Project facilitate focus on several key regulatory steps including polyamine metabolism (Project 1), insulin-like growth factors and their binding proteins (Project 2), progesterone receptor physiology and receptor variants (Project 3), factors controlling invasiveness and metastasis (Project 4), and regulation of responsiveness to estrogens (Project 5). Experiments address testable hypotheses by directly examining specific molecular processes, by evaluating cellular changes, and by examining biologic events such as metastases in animal models. A full understanding of the hormonal control of mitotic processes will enable identification of key steps which are bypassed in the process of evolution to aggressive tumor phenotypes. Data resulting from these studies should allow selection of several key steps for treatment intervention. While more complete blockade of aromatase is a current priority, we expect the proposed studies to identify several other steps, such as ornithine decarboxylase, as targets for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA040011-09
Application #
3093739
Study Section
Special Emphasis Panel (SRC (1G))
Project Start
1985-07-01
Project End
1996-07-31
Budget Start
1993-08-16
Budget End
1994-07-31
Support Year
9
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Hurst, Douglas R; Welch, Danny R (2007) A MSC-ing link in metastasis? Nat Med 13:1289-91
Manni, A; Wechter, R; Verderame, M F et al. (1998) Cooperativity between the polyamine pathway and HER-2neu in transformation of human mammary epithelial cells in culture: role of the MAPK pathway. Int J Cancer 76:563-70
Phillips, K K; White, A E; Hicks, D J et al. (1998) Correlation between reduction of metastasis in the MDA-MB-435 model system and increased expression of the Kai-1 protein. Mol Carcinog 21:111-20
McGary, C T; Pan, Y C; Michel, H et al. (1997) Elevated expression of the neutrophil calcium-binding protein, MRP-14, in metastasis-enhancing neutrophils. Anticancer Res 17:1-6
Masamura, S; Santner, S J; Gimotty, P et al. (1997) Mechanism for maintenance of high breast tumor estradiol concentrations in the absence of ovarian function: role of very high affinity tissue uptake. Breast Cancer Res Treat 42:215-26
Manni, A; Wechter, R; Gilmour, S et al. (1997) Ornithine decarboxylase over-expression stimulates mitogen-activated protein kinase and anchorage-independent growth of human breast epithelial cells. Int J Cancer 70:175-82
Welch, D R (1997) Technical considerations for studying cancer metastasis in vivo. Clin Exp Metastasis 15:272-306
Wei, L L; Norris, B M; Baker, C J (1997) An N-terminally truncated third progesterone receptor protein, PR(C), forms heterodimers with PR(B) but interferes in PR(B)-DNA binding. J Steroid Biochem Mol Biol 62:287-97
Phillips, K K; Welch, D R; Miele, M E et al. (1996) Suppression of MDA-MB-435 breast carcinoma cell metastasis following the introduction of human chromosome 11. Cancer Res 56:1222-7
Manni, A; Buckwalter, E; Etindi, R et al. (1996) Induction of a less aggressive breast cancer phenotype by protein kinase C-alpha and -beta overexpression. Cell Growth Differ 7:1187-98

Showing the most recent 10 out of 96 publications