Trastuzumab in combination with heregulin-activated Her-2 (erbB-2) triggers a receptor-enhanced chemosensitivity effect in the absence of Her-2 overexpression

Javier A. Menendez, Inderjit Mehmi, Ruth Lupu

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Purpose: The decision for treating breast cancer patients with trastuzumab is based on HER-2 amplification and/or overexpression. Methods: Using MCF-7 cells (Her-2 ±) engineered to overexpress heregulin (MCF-7/HRG), a ligand for the Her-2/3/4 network, we investigated whether HRG-induced transactivation of Her-2 affected breast cancer cell sensitivity to chemotherapy and whether trastuzumab trigger receptor-enhanced chemosensitivity (REC) when combined with chemotherapy without Her-2 overexpression. Results: MCF-7/HRG cells were more than 10-fold resistant to the alkylating agent cisplatin (CDDP), while trastuzumab coexposure completely reversed HRG-promoted CDDP resistance. A synergistic interaction between trastuzumab in combination with CDDP (paclitaxel or vincristine) was obtained in MCF-7/HRG cells. Trastuzumab prevented activation of the antiapoptotic and proliferative cascades and inhibited HRG-induced Her-2/3 phosphorylation. CDDP efficacy was enhanced by trastuzumab in cells expressing endogenously high levels of HRG. Conversely, trastuzumab coexposure was ineffective in enhancing chemotherapy efficacy in cells that did not secrete HRG, such as MCF-7 cells overexpressing a structural mutated HRG isoform. Therefore, trastuzumab-induced REC, in the absence of Her-2 overexpression, occurs through the kinase activity of Her-2/3. Interestingly, HRG expression in tumor biopsies from invasive breast carcinomas (n = 189) revealed that, whereas the minority (12%) of Her-2 positive tumors (n = 60; 32%) demonstrated Her-2 phosphorylation, the majority (67%) of HRG-overexpressing and Her-2 tumors (n = 57; 30%) were in active Her-2 status. Conclusion: We demonstrate that assessment of HRG expression and Her-2 activation define a particular breast cancer patient population for which trastuzumab plus CDDP or taxol are extremely efficient without Her-2 overexpression.

Original languageEnglish (US)
Pages (from-to)3735-3746
Number of pages12
JournalJournal of Clinical Oncology
Volume24
Issue number23
DOIs
StatePublished - Aug 10 2006
Externally publishedYes

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Neuregulin-1
MCF-7 Cells
Breast Neoplasms
Paclitaxel
Drug Therapy
histidine-rich proteins
Trastuzumab
Phosphorylation
Neoplasms
Alkylating Agents
Vincristine
Cisplatin
Transcriptional Activation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Trastuzumab in combination with heregulin-activated Her-2 (erbB-2) triggers a receptor-enhanced chemosensitivity effect in the absence of Her-2 overexpression. / Menendez, Javier A.; Mehmi, Inderjit; Lupu, Ruth.

In: Journal of Clinical Oncology, Vol. 24, No. 23, 10.08.2006, p. 3735-3746.

Research output: Contribution to journalArticle

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abstract = "Purpose: The decision for treating breast cancer patients with trastuzumab is based on HER-2 amplification and/or overexpression. Methods: Using MCF-7 cells (Her-2 ±) engineered to overexpress heregulin (MCF-7/HRG), a ligand for the Her-2/3/4 network, we investigated whether HRG-induced transactivation of Her-2 affected breast cancer cell sensitivity to chemotherapy and whether trastuzumab trigger receptor-enhanced chemosensitivity (REC) when combined with chemotherapy without Her-2 overexpression. Results: MCF-7/HRG cells were more than 10-fold resistant to the alkylating agent cisplatin (CDDP), while trastuzumab coexposure completely reversed HRG-promoted CDDP resistance. A synergistic interaction between trastuzumab in combination with CDDP (paclitaxel or vincristine) was obtained in MCF-7/HRG cells. Trastuzumab prevented activation of the antiapoptotic and proliferative cascades and inhibited HRG-induced Her-2/3 phosphorylation. CDDP efficacy was enhanced by trastuzumab in cells expressing endogenously high levels of HRG. Conversely, trastuzumab coexposure was ineffective in enhancing chemotherapy efficacy in cells that did not secrete HRG, such as MCF-7 cells overexpressing a structural mutated HRG isoform. Therefore, trastuzumab-induced REC, in the absence of Her-2 overexpression, occurs through the kinase activity of Her-2/3. Interestingly, HRG expression in tumor biopsies from invasive breast carcinomas (n = 189) revealed that, whereas the minority (12{\%}) of Her-2 positive tumors (n = 60; 32{\%}) demonstrated Her-2 phosphorylation, the majority (67{\%}) of HRG-overexpressing and Her-2 tumors (n = 57; 30{\%}) were in active Her-2 status. Conclusion: We demonstrate that assessment of HRG expression and Her-2 activation define a particular breast cancer patient population for which trastuzumab plus CDDP or taxol are extremely efficient without Her-2 overexpression.",
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