[CANCER RESEARCH57. 3071-3078, August 1. 1997] Perspectives in Cancer Research MCF-7: The First Hormone-responsive Breast Cancer Cell Line' Anait S. Levenson and V. Craig Jordan2 Robert H. Lurie Cancer Center, Northwestern University Medical School, Chicago, Illinois 60611 !ntroduction OnThursday,January2, 1997, Dr. HerbertSoule, the scientistwho developed the MCF-7 breast cancer cell line, died. At the time, we were in the process of writingthis tributeto markthe 25th anniversary of Dr. Soule's remarkableaccomplishment.The cells, derivedfrom a breast cancer patient in the Detroit area and developed at the Michigan CancerFoundation,Detroit,became a standardmodel in hundredsof laboratories around the world. In retrospect, the story of the diverse uses of these cells is really the history of our developing knowledge of hormone-regulatedcell replication, and they provided a unique insight into the endocrine therapyof breast cancer. Our article is offered as a tributeand memorial to Dr. Soule. We will trace research with MCF-7 cells to illustrate the change in our ideas about cell replication and to highlight the advances in our understanding of the signal transduction pathway of estrogen and the molecular biology of estrogen action. All of these advances depended on the unique propertiesof MCF-7 cells. Additionally,it is important to appreciate that the cell system has now found applications in experimental therapeutics, and the results from these studies are being translated to the clinic for the treatment of patients. None of this would have been possible without Dr. Soule's skill as a cell biologist. Characterization The MCF-7 breast cancer cell line was derived from a pleural effusion taken from a patient with metastatic breast cancer (1). The 69-year-old patient had undergone a mastectomy of her right breast for a benign tumor and a radical mastectomy of her left breast for a malignant adenocarcinoma 7 and 3 years, respectively, before primary culture of cells was started.Interestingly,the Soule et aL article (1) notes that local recurrences were controlled for 3 years with radio therapy and hormone therapy. In the days before tamoxifen, the patientwas probablytreatedwith high doses of the syntheticestrogen diethylstilbestrol.Clearly, the disease was very hormone responsive, because it was controlled for three times longer than the 1-year average to be expected. Two months after widespread nodular recur rences occurred, in June of 1970, samples were taken from a pleural effusion for laboratory studies. The cells were proven to be of human origin, and cytogenetic studies indicated a distinct stem line of 88 chromosomes. Dr. Sam Brooks, working with Dr. Soule (2), first described the ER3 in MCF-7 cells by both Scatchard and sucrose density gradient analysis. This was a pivotal discovery. From this point onward, researchacceleratedrapidly. In 1975, Dr. Received 4/10/97; accepted 5/30/97. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18U.S.C.Section1734solelytoindicate thisfact. 1 These studies were supported by NIH Grant CA-56143, Breast Cancer Program Development Grant P11 CA-657634, and the Lynn Sage Breast Cancer Foundation of Northwestern Memorial Hospital, Chicago. 2 To whom requests for reprints should be addressed, at the Robert H. Lutie Cancer Center, Northwestern University Medical School, 303 East Chicago Avenue, Olson Pavilion8258,Chicago, IL60611.Phone:(312)908-4148;Fax:(312)908-1372. 3 The abbreviations used are: ER, estrogen receptor, PGR, progesterone receptor; TGF, transforming growth factor; [OF, insulin-like growth factor. Marc Lippman (3) demonstrated that the antiestrogen tamoxifen in hibited the growth of MCF-7 cells, but the inhibition could be re versed by estrogen. The drug was classified as a competitive inhibitor of estrogen action, but at high concentrationstamoxifen killed cells. Because these results appeared to parallel the emerging clinical oh servations (4), Lippman (3) went on to predict a future path for endocrine research: “Thepotential value of a hormone-dependent human breast cancer in long term tissue culture for the study of mechanism(s) by which steroid hormones exert their trophic effects is significant, particularlyin view of the likelihood of obtainingregula tory variantsor mutantswhich are hormone independent.― At about the same time, KathrynHorwitz,who was completingher Ph.D. in the late Dr. Bill McGuire's laboratory, identified the receptors for glu cocorticoids, progestins, and androgens, as well as the ER (5). She concluded, “MCF-7 may be an excellent in vitro model for studying the mechanismof tumorresponse to endocrinetherapyas well as the complex relationshipsbetween bindingand biological actions of these hormones― (5). The predictionsfrom both researchprogramswere to be proved correct over the next 2 decades. Horwitz and McGuire focused initially on the regulation of PgR synthesis in MCF-7 cells by estrogens and antiestrogens. They devel oped a large body of evidence to associate processing (destruction)of nuclearreceptorcomplexes with the initiationof PgR synthesis (6, 7). This work paralleled their suggestion of using PgR assays as a predictive test for hormone-dependent breast cancer (8). Turning to the effects of antiestrogens,Horwitz et a!. (9) found thattamoxifen is sufficiently estrogenic to initiate PgR synthesis by itself. The estro genic properties of tamoxifen would subsequently be importantto explain the additionalbenefits of tamoxifen on bones and lipids and the possible development of drug resistance (10). However, at that time in the late l970s, work on the antiproliferative actions of antics trogens was of paramountimportance. Tamoxifen and other corn pounds were shown to inhibit replication (11). Drs. Rob Sutherland (12, 13) and Kent Osborne (14, 15) would demonstrate subsequently, using MCF-7 cells, that tamoxifen produces a reversible block in the G1 phase of the cell cycle. Despite the interesting findings with antiestrogens, the central focus of laboratoryresearchin the 1970s andearly 1980s was to prove that estrogen actually stimulated tumor growth directly. Dogma predicted that the MCF-7 ER-positive cell line should grow faster with exoge nous estrogen. The experiment could be accomplished routinely if cells first were treated with antiestrogens for a few days. Estrogen could “rescue― antiestrogen-blockedcells (3), but the effects of es trogen alone were less dramatic.Here was a paradox. Cells Grown in Estrogen Although Lipprnan'sgroup consistently demonstratedstimulatory effects with estrogenusing [3H]thymidineincorporationas a method of monitoringDNA replication(3, 11, 16), otherswere unableto show profound effects on cell proliferation (17—19). This led to intense debate (20) and also to the suggestion that estrogen really produced 3071 Research. on November 28, 2021. © 1997 American Association for Cancer cancerres.aacrjournals.org Downloaded from