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.
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