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Induction of Sensitivity to Doxorubicin and Etoposide by Transfection of MCF-7 Breast Cancer Cells with Heregulin F3-2’

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Induction of Sensitivity to Doxorubicin and Etoposide by Transfection of MCF-7 Breast Cancer Cells with Heregulin F3-2’ Vol. 4, 1005-1012, April 1998 Clinical Cancer Research 1005 Induction of Sensitivity to Doxorubicin and Etoposide by Transfection of MCF-7 Breast Cancer Cells with Heregulin f3-2’ Lyndsay N. Harris, Li Yang, Careen Tang, heregulin. topo Ha mRNA and protein (total protein and Dajun Yang, and Ruth Lupu2 enzymatic decatenating activity) were found to be up-regu- lated in heregulin -2-transfected cells. Moreover, topo IIa Duke University Medical Center, Durham, North Carolina 20502 [L. N. H., L. Y.]; Lombardi Cancer Research Center, Washington, promoter activity was also modestly increased in heregulin D.C. 20007 [C. T., D. Y.]; and University of California Berkeley, 3-2-transfected cells. Because up-regulation of topo Ha in Berkeley, California 94720 [R. L.] vitro and in clinical specimens is associated with increased response to doxorubicin (presumptively by an increase in drug substrate), this may be the mechanism of the increased ABSTRACT sensitivity to doxorubicin seen in heregulin -2-transfected HER2 (erbB-2) proto-oncogene amplification and/or cells. This implies that activation of HER2 or one of the overexpression correlate with poor prognosis in many ma- other members of the receptor family may increase sensitiv- lignancies. The precise biological role of this oncogenic sig- ityto doxorubicin by up-regulation of topo ha. naling pathway (which also involves the HER4 gene) in This finding suggests the use of receptor/ligand expres- breast cancer is unclear. One property conferred by this sion to direct patient-specific therapeutic choices (e.g., doxo- oncogene relates to response to drug therapy. Clinical stud- rubicin versus alkylator-based regimens) and the use of ies support an association between HER2 overexpression biological agents (such as heregulin) in combination with and resistance to alkylating agents (cisplatinum and cyclo- certain chemotherapeutic agents to enhance response to phosphamide). Data from the Cancer and Leukemia Group treatment in breast cancer patients. B 8869/8541 study indicate enhanced dose responsiveness to doxorubicin (Adriamycin) in patients who overexpress the INTRODUCTION HER2 receptor. Oncogene activation has been studied in an attempt to Heregulin 3-2, a naturally occurring ligand that acti- define a molecular correlation for the clinical behavior of breast yates the HER2 receptor by inducing its heterodimerization cancer (1). Numerous studies have indicated a role for the HER2 with the HER4 receptor, has recently been cloned. The oncogene in breast cancer and its correlation with poor progno- ability of this ligand to phosphorylate the HER2 receptor sis (2, 3). HER2 is overexpressed in nearly 30% of human breast exogenously allows us to study the effect of HER2 activation cancer specimens and is associated with poor outcome in most on cancer cell behavior. To study the relationship between studies, particularly in node-positive patients. chemotherapy response and activation of HER2, MCF-7 Several possible ligands that modulate p18SHER2 signal cells expressing biologically active heregulin were assessed transduction in human breast cancer cells or NIH-3T3 cells for response to doxorubicin and etoposide, both of which are overexpressing HER2 have been characterized. These include topoisomerase lla (topo Ha) inhibitors. Several clones show the 45-kDa human heregulin (4), a 25-kDa neu/erbB-2 ligand markedly increased sensitivity to these drugs. In addition, growth factor from bovine kidney (5), the rat Neu differentiation the same wild-type MCF-7 cells transfected with heregulin factor (6), and the molecule gp3O (7, 8). Heregulin 3-2 has -2 under the control of an inducible promoter also show recently been cloned and shown to activate the HER2 receptor this dose-response relationship to doxorubicin after the ex- through heterodimerization with the HER4 receptor (4, 9). pression of heregulin -2 is activated by zinc. The modula- Hence, this molecule can induce phosphorylation of the HER2 tion of topo Ha was studied in the cell lines transfected with receptor without requiring receptor overexpression. Because receptor overexpression and homodimerization are difficult to manipulate in vitro, activation of the HER2 receptor has been studied by construction of HER2-epidermal growth factor re- Received 7/16/97; revised 12/22/97; accepted 1/16/98. ceptor chimeras activated by epidermal growth factor, a situa- The costs of publication of this article were defrayed in part by the tion that is somewhat artificial. Using heregulin 3-2, the effects payment of page charges. This article must therefore be hereby marked of HER2 activation can be studied in vitro and in vivo using advertisement in accordance with 18 U.S.C. Section 1734 solely to ligand activation. indicate this fact. The relationship between HER2 receptor overexpression 1 Supported by the Specialized Program for Research Excellence in Breast Cancer fellowship program (L. N. H.) and The Komen Founda- and drug sensitivity is of considerable interest, because this may tion, Race for the Cure, and Concern Foundation for Cancer Research allow a better prediction of response to chemotherapy. HER2 (R. L.). activation has been associated with tumor cell resistance to 2 To whom requests for reprints should be addressed, at Lawrence several cytotoxic compounds, including the chemotherapy agent Berkeley National Laboratories, University of California Berkeley, 1 Cyclotron Road, Building 934, Berkeley, CA 94710. Phone: (510) cisplatinum (10), tumor necrosis factor (1 1), the action of nat- 486-6874; Fax: (510) 486-7289. ural killer cells (12), and tamoxifen (13, 14) on breast cancer Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 1998 American Association for Cancer Research. 1006 Induction of Sensitivity to Chemotherapy by Heregulin cells. However, increased response to anthracycline (e.g., doxo- cytomegalovirus early gene promoter) with subsequent selection rubicin)-containing treatment has also been correlated with of stable pooled (T4 and T5) and single-clone (T6, T7, and 52) HER2 overexpression (15, 16). Further understanding of the populations (33)4 These MCF-7/T clones were used for all molecular mechanisms behind this differential sensitivity may experiments, except as indicated. In addition, vector-transfected lead to the selection of optimal chemotherapy in these otherwise cells (MCF-71V) and MCF-7IWT cells were used as controls. bad-prognosis tumors. MCF-7/ADR cells (Ken Cowan, NIH, Bethesda, MD) were used It is thought that doxorubicin acts by binding to topo lIes.3 as a doxorubicin-resistant cell line. MCF-7lheregulin-MT cells topo lIes is a DNA-modifying enzyme that binds to the double were created by transfection of MCF-7 cells with heregulin 3-2 helix to release torsional stress and create double-strand breaks under the control of a zinc-inducible MT promoter. Cells were that allow replication to occur. Drugs that interfere with topo lIes stably transfected and selected as described above.4 Character- include the anthracyclines (doxorubicin and daunorubicin), VP- ization of cell lines as high, medium, or low expressors refers to 16, teniposide, and amascarine. These agents seem to act by the mRNA levels of heregulin 3-2 after induction with zinc binding covalently with topo lies after double-strand breaks have chloride (100 IJ.M) for 2 days and measurement by RNase occurred and induce lethal cellular damage. Increased topo lies protection (data not shown). In addition, the antisense sequence expression is associated with sensitivity to these agents, both in of heregulin 3-2 under control of the MT promoter was trans- cell lines and tumors, presumably due to the increased substrate fected into parental MCF-7 cells as a control. The antisense on which the drug may act (17, 18). topo lies, which occurs in clone had no detectable levels of heregulin 3-2 mRNA. the same amplicon on chromosome I 7 as HER2, has been Anchorage-dependent Cytotoxicity Assays. MCF-7/ shown to be altered by amplification, point mutation, and dde- WT, MCF-7/ADR, MCF-7/T, and MCF-71V cells were plated at tion in breast cancers that overexpress HER2 (19). A recent 1000-2000 cells/well in IMEM + 10% FCS in a 96-well study demonstrated that increased expression of topo lies is microtiter dish on day 0. Cells were treated with increasing associated with c-erbB-2 (HER2) overexpression in breast can- concentrations of doxorubicin (0.001-10 jiM) or VP-l6 (0.1- cer (20). Therefore, it seems that topo lies may be commonly 1000 p.M) with continuous exposure and assayed for viability on overexpressed with this oncogene, leading to a mechanism for day 7 (at confluence of control sample). Cell viability was increase in sensitivity to topo lIes inhibitors. assessed by XTT assay (2 1 ). Specifically, XTT (Polysciences, Although clinical studies imply a dose-response relation- Inc.) solution was prepared at 1 .0 mg/mi in prewarmed IMEM- ship between receptor overexpression and response to anthra- phenol Red-free media, incubated for 20 mm, and incubated cycline treatment, studying this phenomenon in vitro has been with 10 i.l of phenazine methosulfate solution (1 .53 mg/mi) per problematic. Cell lines that overexpress HER2 have been exam- milliliter of XTT solution for 20 mm. This solution (50 il) was med for differences in drug sensitivity/resistance with varying added to 200 p.! of IMEM + phenol Red-free media in micro- results. The ability to modulate HER2 activation using heregulin titer plates containing treated cells. The plates were incubated at 3-2, along with the unelucidated relationship between HER2 37#{176}Cfor 4 h, shaken for 20 mm, and read at 450 nm on an overexpression and response to doxorubicin, led us to explore ELISA plate reader. Similar assays were performed for MCF- heregulin 3-2-mediated activation of the HER2 receptor as it 7/MT cells that were incubated before plating in 100 i.M ZnC12 relates to drug sensitivity. To study whether activation of HER2 or serum-containing media alone.
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