We have proposed previously that estrogens promote mammary tumor cell growth in vivo via induction of a new group of mediator growth factors tentatively designated estromedins. These mitogenic polypeptides are either endocrine factors that are produced in one target tissue (under estrogen control), secreted into plasma and act on distant target cells, or instead, are locally acting autocrine (autostimulatory) forms that are released and act in the target tissue in response to estrogen stimulation. In ongoing studies of the endocrine mechanism, we have purified mg amounts of three new mammary tumor cell growth factors from sheep uterus, mature ewe kidney and whole sheep pituitaries. These activities are all acetic acid and heat stable peptides of Mr = 3,900 to 4,200 and are shown to be distinct by biochemical and biological analyses. In parallel studies, we have shown that the MTW9/PL rat mammary tumor cells in culture possess an estradiol inducible, acetic acid and heat stable autostimulatory factor (Mr = 4,200) that we have partially purified in mg amounts from these tumors growing in W/Fu rats. Complete purification of this autocrine activity is now in progress using new HPLC methods. In this application we propose to define the role of these growth factors in estrogen responsive and autonomous mammary tumor growth.
The specific aims are (1) to determine the conditions for raising monoclonal antibodies to the purified growth factors using in vitro immunization methods, (2) to determine whether the growth factors are immunologically distinguishable, (3) to determine whether the antibodies to the endocrine forms of estromedins are able to inhibit mammary estrogen responsive and/or autonomous mammary tumor cell growth in W/Fu rats, and finally (4) to better define the role of autocrine (autostimulatory) factors in conversion of estrogen-responsive growth to autonomy. It is our working hypothesis that estrogen-responsive mammary tumor growth is dependent upon endocrine and autocrine factors, whereas, autonomous tumor growth requires only autocrine factors. The studies proposed are aimed at establishing whether antigrowth factor monoclonal antibodies are effective therapeutic agents for mammary tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA038024-03
Application #
3176013
Study Section
Biochemical Endocrinology Study Section (BCE)
Project Start
1984-08-01
Project End
1988-03-30
Budget Start
1986-08-01
Budget End
1988-03-30
Support Year
3
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
Eby, J E; Sato, H; Sirbasku, D A (1993) Apotransferrin stimulation of thyroid hormone dependent rat pituitary tumor cell growth in serum-free chemically defined medium: role of FE(III) chelation. J Cell Physiol 156:588-600
Eby, J E; Sato, H; Sirbasku, D A (1992) Preparation of iron-deficient tissue culture medium by deferoxamine-sepharose treatment and application to the differential actions of apotransferrin and diferric transferrin. Anal Biochem 203:317-25
Sato, H; Eby, J E; Pakala, R et al. (1992) Apotransferrins from several species promote thyroid hormone-dependent rat pituitary tumor cell growth in iron-restricted serum-free defined culture. Mol Cell Endocrinol 83:239-51
Sirbasku, D A; Pakala, R; Sato, H et al. (1992) Thyroid hormone and apotransferrin regulation of growth hormone secretion by GH1 rat pituitary tumor cells in iron restricted serum-free defined medium. In Vitro Cell Dev Biol 28A:67-71
Sato, H; Eby, J E; Sirbasku, D A (1991) Iron is deleterious to hormone-responsive pituitary cell growth in serum-free defined medium. In Vitro Cell Dev Biol 27A:599-602
Sirbasku, D A; Stewart, B H; Pakala, R et al. (1991) Purification of an equine apotransferrin variant (thyromedin) essential for thyroid hormone dependent growth of GH1 rat pituitary tumor cells in chemically defined culture. Biochemistry 30:295-304
Sirbasku, D A; Pakala, R; Sato, H et al. (1991) Thyroid hormone dependent pituitary tumor cell growth in serum-free chemically defined culture. A new regulatory role for apotransferrin. Biochemistry 30:7466-77
Sirbasku, D A; Pakala, R; Sato, H et al. (1991) Thyroid hormone regulation of rat pituitary tumor cell growth: a new role for apotransferrin as an autocrine thyromedin. Mol Cell Endocrinol 77:C47-55
Karey, K P; Marquardt, H; Sirbasku, D A (1989) Human platelet-derived mitogens. I. Identification of insulinlike growth factors I and II by purification and N alpha amino acid sequence analysis. Blood 74:1084-92
Karey, K P; Sirbasku, D A (1989) Human platelet-derived mitogens. II. Subcellular localization of insulinlike growth factor I to the alpha-granule and release in response to thrombin. Blood 74:1093-100

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