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| ESTROGEN-DEPENDENT, TAMOXIFEN-RESISTANT TUMORIGENIC GROWTH OF MCF-7 CELLS TRANSFECTED WITH HER2/NEU |
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| Author(s): BENZ CC, SCOTT GK, SARUP JC, JOHNSON RM, TRIPATHY D, CORONADO E, SHEPARD HM, OSBORNE CK |
| Source: BREAST CANCER RESEARCH AND TREATMENT Volume: 24 Issue: 2 Pages: 85-95 Published: 1992 |
| Times Cited: 218 References: 26 |
| Abstract: Since the poor prognosis associated with HER2 amplified breast cancers might be explained by a mechanistic association between p185HER2 overexpression and therapeutic resistance, we assessed the chemo-endocrine sensitivity of estrogen receptor (ER) containing MCF-7 breast cancer cells transfected with full-length HER2 cDNA. Of the 36 isolated MCF/HER2 subclones, 7 were found to overexpress p185HER2 surface receptor at levels 3 to 45-fold greater than parental or control transfected cells (MCF/neo). The overexpressing transfectants possessed increased inositol-1,4,5-trisphosphate-3'-kinase activity comparable to enzyme activity in the endogenously HER2 amplified breast cancer cell lines SK-Br-3 and BT-474. The anti-p185HER2 monoclonal antibody and receptor-specific partial agonist, muMAb4D5 (4D5), known to inhibit growth of SK-Br-3 and BT-474 cells, produced no significant growth inhibitory effect on any of the transfectants including the 45-fold overexpressing MCF/HER2-18 cells which were studied in greater detail. MCF/HER2-18 cells contained at least partially functioning exogenous receptor since 4D5 (3 mug/ml) specifically stimulated phosphorylation of p185HER2 and its co-precipitating ptyr56 substrate within 5 min, and this was followed at 1 h by a transient induction of c-myc but not c-fos mRNA. ER content and the in vitro sensitivity of MCF/HER2-18 cells to 5-fluorouracil and adriamycin were identical to those of control transfectants and parental cells. However, these highly overexpressing transfectants had acquired low level (2 to 4 fold) resistance to cisplatin and were no longer sensitive to the antiestrogen tamoxifen (TAM). To compare the hormone-dependent tumorigenicity of the HER2 transfectants, MCF/HER2-18 and control cells (MCF, MCF/neo-3) were implanted into ovariectomized athymic nude mice. No tumors were produced in the absence of estradiol (E2) administration. In E2 supplemented mice, MCF/HER2-18 tumors grew most rapidly. When E2 treatment was stopped and daily TAM injections were initiated, MCF-7 and MCF/neo-3 tumor growth ceased immediately, while MCF/HER2-18 tumors continued to show an accelerated growth rate lasting weeks. This pattern of hormone-dependent, TAM-resistant growth exhibited by the MCF/HER2-18 tumors in nude mice supports the possibility that p185HER2 overexpression in human breast cancers may be linked to therapeutic resistance. |
| Document Type: Article |
| Language: English |
| Reprint Address: BENZ, CC (reprint author), UNIV CALIF SAN FRANCISCO, CANC RES INST, M-1282, SAN FRANCISCO, CA 94143 USA |
Addresses:
1. GENENTECH INC, DEPT DEV BIOL, S SAN FRANCISCO, CA 94080 USA
2. UNIV TEXAS, HLTH SCI CTR, DEPT MED, SAN ANTONIO, TX 78284 USA |
| Publisher: KLUWER ACADEMIC PUBL, SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS |
| Subject Category: Oncology |
| IDS Number: KL908 |
| ISSN: 0167-6806 |
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