FUNCTIONAL STUDY OF A CARCINOMA-ASSOCIATED MUCIN MUC-1

Project: Research project

Description

Our goal is to understand the function of the tumor-associated mucin MUC1
in the progression of neoplasia in the mammary gland. The MUC1 protein
(also called PEM, polymorphic epithelial mucin) is a heavily glycosylated
transmembrane mucin glycoprotein that is highly expressed and aberrantly
glycosylated by the majority of carcinomas and in particular, by >92% of
primary and metastatic breast cancers. The MUC1 protein is a large, rod-
like molecule, extending more than 250 nm beyond the cell surface, and it
is often sialylated. The structural and biochemical characteristics may
enable this protein to act by masking cell surface proteins, possibly
those involved in adhesion or immune recognition. Our hypothesis is that
expression of this protein benefits tumor cells and their metastatic
counterparts, perhaps by reducing the adhesive properties of cells or by
providing a protective layer around cells which may shield them from
immune surveillance. MUC1 protein is also present at the apical surfaces
of normal simple epithelial cells and is developmentally regulated,
appearing initially about the time of lumen formation during organogenesis
(day 11 in the mouse). Our hypothesis is that MUC1 may be involved in
epithelial morphogenesis, perhaps acting to mask adhesive molecules
present on the cell surface and aiding in the formation of a lumen. Since
mammary gland cancer in the mouse closely resembles human breast cancer,
our proposed experiments will allow us to analyze the functional role of
Muc-l (the human gene designation is MUC1; the mouse gene is Muc- l) in
the progression of neoplasia and in development. The current proposal will
directly test the hypotheses by addressing the following specific aims:
(l) By using gene targeting in embryonic stem cells, we will make a mouse
strain with a mutated Muc-l gene, thus generating animals lacking Muc-l
protein for testing its function in tumor progression and development (2)
We will determine the effect of Muc-l deficiency on epithelial
organogenesis, since it is important to understand its function in normal
tissues as well as in cancer. (3) We will mate the mutant mice with
transgenic mice that develop mammary gland tumors or induce tumors in
these mice with chemicals or radiation to determine the effect of Muc-l
deficiency on tumor formation and progression (growth and
differentiation). (4) We will generate tumors that metastasize, thus
enabling an analysis of the effect of the Muc-l protein on the rate of
metastasis, percentage of tumors that metastasize, and organ specificity
of metastatic lesions. (5) We will examine the susceptibility of tumors
developing in the Muc-l-deficient and control mice to lysis by immune
effector cells (NK cells and cytotoxic T lymphocytes). Our findings should
be relevant to understanding more about the progression of breast cancer
with the hope, ultimately, of better modulating progression of the
disease.
StatusFinished
Effective start/end date7/1/945/31/15

Funding

  • National Institutes of Health: $365,025.00
  • National Institutes of Health
  • National Institutes of Health: $372,387.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $365,025.00
  • National Institutes of Health: $361,215.00
  • National Institutes of Health: $220,631.00
  • National Institutes of Health: $361,215.00
  • National Institutes of Health: $342,705.00
  • National Institutes of Health: $346,110.00
  • National Institutes of Health
  • National Institutes of Health: $350,378.00
  • National Institutes of Health: $356,447.00
  • National Institutes of Health: $312,457.00
  • National Institutes of Health: $339,542.00
  • National Institutes of Health: $346,110.00
  • National Institutes of Health: $353,044.00
  • National Institutes of Health: $342,180.00
  • National Institutes of Health: $284,933.00

Fingerprint

Mucins
Mucin-1
Carcinoma
Neoplasms
Human Mammary Glands
Tail
Proteins
Neoplasm Metastasis
Breast Neoplasms
Carcinogenesis
Epithelium
Signal Transduction
beta Catenin
Adhesives
Tyrosine
Neoplasm Antigens
Phosphotransferases
Growth
Cell Differentiation
Protein Kinase C-delta

ASJC

  • Medicine(all)