Research Papers:

Heregulin-expressing HER2-positive breast and gastric cancer exhibited heterogeneous susceptibility to the anti-HER2 agents lapatinib, trastuzumab and T-DM1

Yoshikane Nonagase, Kimio Yonesaka, Hisato Kawakami, Satomi Watanabe, Koji Haratani, Takayuki Takahama, Naoki Takegawa, Hiroto Ueda, Junko Tanizaki, Hidetoshi Hayashi, Takeshi Yoshida, Masayuki Takeda, Yasutaka Chiba, Takao Tamura, Kazuhiko Nakagawa and Junji Tsurutani _

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Oncotarget. 2016; 7:84860-84871. https://doi.org/10.18632/oncotarget.12743

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Yoshikane Nonagase1, Kimio Yonesaka1, Hisato Kawakami1, Satomi Watanabe1, Koji Haratani1, Takayuki Takahama1, Naoki Takegawa1, Hiroto Ueda1, Junko Tanizaki1, Hidetoshi Hayashi1, Takeshi Yoshida1, Masayuki Takeda1, Yasutaka Chiba2, Takao Tamura1, Kazuhiko Nakagawa1, Junji Tsurutani1

1Department of Medical Oncology, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan

2Clinical Research Center, Kindai University Faculty of Medicine, Osakasayama, Osaka, Japan

Correspondence to:

Junji Tsurutani, email: [email protected]

Keywords: HER2, T-DM1, resistance, heregulin, breast cancer

Received: March 28, 2016    Accepted: October 01, 2016    Published: October 19, 2016


Background: Overexpression of heregulin, a HER3 ligand, is one mechanism that confers resistance to the anti-HER2 agents trastuzumab and lapatinib. We investigated the impact of heregulin expression on the efficacy of HER2-targeted therapeutic agents, including trastuzumab, trastuzumab emtansine (T-DM1) and lapatinib, in vitro and in vivo and evaluated the heregulin messenger RNA (mRNA) levels in specimens from patients with HER2-positive breast or gastric cancer.

Results: Cell proliferation and apoptosis assays demonstrated that heregulin conferred robust resistance to lapatinib and trastuzumab via HER3-Akt pathway activation followed by survivin overexpression; however, heregulin conferred minimal or no resistance to T-DM1 and paclitaxel. The heregulin mRNA level of one of 10 patients was up-regulated after the acquisition of resistance to trastuzumab-based therapy.

Materials and Methods: SK-BR-3, NCI-N87, BT-474, MDA-MB-453, HCC1954, SNU-216 and 4-1ST cells were pharmacologically treated with recombinant heregulin or transfected with the heregulin gene. We also assessed the expression of heregulin mRNA in HER2-positive breast or gastric cancer samples before and after trastuzumab-based therapy using a RT-PCR-based method.

Conclusions: mRNA up-regulation of heregulin was observed in clinical breast cancer specimens during trastuzumab-based treatment, but heregulin overexpression had a limited effect on the sensitivity to T-DM1 in vitro and in vivo.

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