Project: Research project

Project Details


DESCRIPTION: This project will focus on the role of activation of polyamine
biosynthesis and MAPK signaling cascade (by either oncogenic ras or
HER-2neu) in breast cancer development. The rationale for these studies is
provided by (1) Dr. Manni's preliminary data suggestive of a role for
polyamines in mammary carcinogenesis, (2) the demonstrated cooperativity
between ras signalling and polyamines in several models of malignant
transformation, (3) the preliminary data showing cooperativity between
HER-2neu signaling and polyamines in mammary carcinogenesis, and (4) the
recent finding by the applicant that ODC overexpression increases MAPK
activity in mammary epithelial cells. Furthermore, the investigator will
test the importance of expression of a functional estrogen receptor in
ras/HER-2neu and/or polyamine-mediated mammary carcinogenesis. He will
conduct experiments in the spontaneously immortalized but non-tumorigenic
MCF-10A and HMT-3522 human breast epithelial cell lines. Specifically: (1)
He will determine the influence of overexpression of ornithine decarboxylase
(ODC) (the first rate-limiting enzyme in polyamine biosynthesis)
individually and in combination with activation of the MAPK cascade (by
either ras or HER2-neu) on in vitro and in vivo features of transformation.
(2) He will determine the role of the MAPK cascade pathway in mediating
polyamines and/or ras/HER-2neu mediated effects by transfecting our cells
with constitutively active and dominant negative mutants of several kinases
belonging to this signalling cascade (e.g. Raf-1, MEK, ERK-1, ERK-2). (3)
He will take advantage of the recent generation of ER transfected MCF-10A
and HMT-3522 cell lines which express a functional ER to test the possible
cooperativity between hormonal and oncogenic signals in the malignant
transformation of human breast epithelial cells. (4) He will evaluate the
"cross-talk" at the transcriptional level between the estrogen receptor
pathway and ras/HER-2neu/ polyamine-mediated signaling as it relates to
mammary carcinogenesis. It is anticipated that the results of the proposed
experiments will provide new insights into the mechanisms subserving the
cooperativity between estrogens and classic oncogenic signals in inducing
transformation of normal human breast epithelial cells.
Effective start/end date4/1/981/31/02


  • National Cancer Institute
  • National Cancer Institute: $243,571.00
  • National Cancer Institute
  • National Cancer Institute: $237,617.00


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