The status of the 66-kDa human estrogen receptor-␣ (hER-␣66) is a critical determinant in the assessment of the prognosis and in the design of treatment strategies of human breast cancer. Recently, we cloned the cDNA of an alternatively spliced variant of hER-␣66, termed hER-␣36; the predicted protein lacks both transcriptional activation domains of hER-␣66 but retains its DNA-binding domain, partial dimerization, and ligand-binding domains and three potential myristoylation sites located near the N terminus. These findings thus predict that hER-␣36 functions very differently from hER-␣66 in response to estrogen signaling. We now demonstrate that hER-␣36 inhibits the estrogen-dependent and estrogen-independent transactivation activities of hER-␣66 and hER-␤. We further demonstrate that hER-␣36 is predominantly associated with the plasma membrane where it transduces both estrogen-and antiestrogen-dependent activation of the mitogen-activated protein kinase͞extracellular signal-regulated kinase signaling pathway and stimulates cell growth. We conclude that hER-␣36 is a predominantly membrane-based, unique alternatively spliced variant of hER-␣66 that acts as a dominant-negative effector of both estrogen-dependent and estrogen-independent transactivation functions signaled through hER-␣66 and ER-␤; it also transduces membrane-initiated estrogen-dependent activation of the mitogenactivated protein kinase͞extracellular signal-regulated kinase mitogenic signaling pathway. The estrogen and antiestrogen signaling pathways mediated by hER-␣36 provide an alternative explanation for why some human breast cancers are resistant to and others are worsened by antiestrogen therapy; the data suggest that hER-␣36 also may be an important marker to direct therapy in human breast cancers, and perhaps hER-␣36 also may transduce estrogen-dependent signaling in other estrogen target tissues.breast cancer ͉ mitogen-activated protein kinase͞extracellular signal-regulated kinase (MAPK͞ERK) ͉ membrane antiestrogen signaling ͉ membrane estrogen signaling B reast cancer is the second-most-common cause of mortality in women in the United States; the toll in human life is particularly devastating because breast cancer strikes women at times of highest productivity and in the years of childbearing and rearing of family. This toll on morbidity and human life continues despite great progress in the diagnosis and development of treatment strategies in human breast cancer, leaving as a high priority the solution to the many remaining questions in understanding the mechanisms that drive breast cancer.

A partial amino acid sequence of human platelet-derived growth factor, the major mitogen in serum for cells of mesenchymal origin, has been determined. A region of 104 contiguous amino acids shows virtual identity with the predicted sequence of p28sis, the putative transforming protein of simian sarcoma virus (SSV). This similarity suggests a mechanism for transformation by SSV and other agents, involving expression of growth factors.

A heparin binding mitogenic protein isolated from bovine uterus shares NH2-terminal amino acid sequence with a protein isolated from newborn rat brain. The cDNA's of the bovine, human, and rat genes have been isolated and encode extraordinarily conserved proteins unrelated to known growth or neurotrophic factors, although identity of nearly 50 percent has been found with the predicted sequence of a retinoic acid induced transcript in differentiating mouse embryonal carcinoma cells. Lysates of COS-7 cells transiently expressing this protein were mitogenic for NRK cells and initiated neurite outgrowth from mixed cultures of embryonic rat brain cells. RNA transcripts encoding this protein were widely distributed in tissues and were developmentally regulated. This protein, previously designated as heparin binding growth factor (HBGF)-8, is now renamed pleiotrophin (PTN) to reflect its diverse activities. PTN may be the first member of a family of developmentally regulated cytokines.

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