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Ref Type Journal Article
PMID (29963236)
Authors Mishra R, Alanazi S, Yuan L, Solomon T, Thaker TM, Jura N, Garrett JT
Title Activating HER3 mutations in breast cancer.
Journal Vol Issue Date Pages Journal Short Title
Oncotarget 9 45 2018 Jun 12 27773-27788 Oncotarget
URL
Abstract Text Recent studies have highlighted a role of HER3 in ER and HER2-driven breast cancers. We sought to investigate the role of patient-derived HER3 mutations in ER+ and HER2+ breast cancer cells using ectopic expression of HER3 mutants. We found that HER3T355I mutant is activating with increased cell proliferation in ER+ T47D and MCF-7 breast cancer cells lacking HER2 over-expression. Immunoblotting and receptor tyrosine kinase array results indicated that T47D and MCF-7 cells expressing HER3T355I had increased p-HER4 and p-HER1 expression. Our data showed that HER3T355I induced cell proliferation is via HER4/HER1-dependent ERK1/2 and cyclinD1 mediated pathways in ER+ cells. ERα expression is upregulated in ER+ cells expressing HER3T355I mutant. We noted crosstalk between ERα and HER3 in T47D cells. Several HER3 mutants (F94L, G284R, D297Y, T355I, and E1261A) acquired a gain-of-function phenotype in MCF10AHER2 cells and were resistant to lapatinib. These mutants increased HER2-HER3 heterodimerization. Knocking down HER3 from ovarian and colorectal cancers with endogenous HER3 mutations abrogated cancer cell proliferation. Overall, this study provides the first systematic assessment of how mutations in HER3 affect response of ER+ and HER2+ breast cancers to clinically relevant inhibitors and finds that HER3 mutations can be activating independent of HER2 over-expression.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
ERBB3 D297Y missense unknown ERBB3 (HER3) D297Y lies within the extracellular domain of the Erbb3 (Her3) protein (UniProt.org). The functional effect of D297Y is conflicting as it demonstrates increased cell proliferation, but not elevated downstream signaling in ER-positive breast cancer cells; however, leads to increased cell proliferation and downstream signaling in Erbb2 (Her2)-overexpressing cells relative to wild-type (PMID: 29963236), and in another study results in similar cell proliferation and viability levels as wild-type Erbb3 (Her3) (PMID: 29533785), and therefore, its effect on Erbb3 (Her3) protein function is unknown.
ERBB3 D313H missense no effect - predicted ERBB3 (HER3) D313H lies within the extracellular domain of the Erbb3 (Her3) protein (PMID: 29963236). D313H results in cell proliferation levels similar to wild-type Erbb3 (Her3) in culture (PMID: 29963236), and therefore, is predicted to have no effect on Erbb3 (Her3) protein function.
ERBB3 E1261A missense unknown ERBB3 (HER3) E1261A lies within the cytoplasmic domain of the Erbb3 (Her3) protein (UniProt.org). The functional effect of E1261A is conflicting as it demonstrates cell proliferation levels similar to wild-type Erbb3 (Her3) in ER-positive breast cancer cells, but results in both increased cell proliferation and Erbb3 (Her3) phosphorylation relative to wild-type in Erbb2 (Her2)-overexpressing breast cancer cells (PMID: 29963236), and therefore, its effect on Erbb3 (Her3) protein function is unknown.
ERBB3 F94L missense unknown ERBB3 (HER3) F94L lies within the extracellular domain of the Erbb3 (Her3) protein (PMID: 29963236). The functional effect of F94L is conflicting as it does not result in increased cell proliferation relative to wild-type Erbb3 (Her3) in ER-positive breast cancer cells (PMID: 29963236) and does not lead to increased downstream signaling or cell proliferation in Erbb2 (Her2)-positive breast cancer cells in culture (PMID: 38751013), but in another study results in elevated cell proliferation in Erbb2 (Her2)-overexpressing cells in culture (PMID: 29963236), and therefore, its effect on Erbb3 (Her3) protein function is unknown.
ERBB3 G284R missense unknown ERBB3 (HER3) G284R lies within the extracellular domain of the Erbb3 (Her3) protein (UniProt.org). G284R results in increased phosphorylation of Akt and Erk, as well as oncogenic transformation of Erbb2 (Her2)-expressing cells relative to wild-type Erbb3 (Her3) (PMID: 23680147), leads to increased cell proliferation in Erbb2 (Her2)-overexpressing cells in culture (PMID: 29963236), and results in a modest increase in Erbb2 phosphorylation and IL3-independent growth when expressed with ERBB2 (HER2) V956R in culture (PMID: 38806620), but has not been individually characterized and therefore, its effect on Erbb3 (Her3) protein function is unknown.
ERBB3 K329T missense no effect - predicted ERBB3 (HER3) K329T lies within the extracellular domain of the Erbb3 (Her3) protein (PMID: 29963236). K329T results in cell proliferation levels similar to wild-type Erbb3 (Her3) in culture (PMID: 29963236), and therefore, is predicted to have no effect on Erbb3 (Her3) protein function.
ERBB3 K742E missense unknown ERBB3 (HER3) K742E lies within the protein kinase domain of the Erbb3 (Her3) protein (UniProt.org). K742E has been identified in the scientific literature (PMID: 29963236), but has not been biochemically characterized and therefore, its effect on Erbb3 (Her3) protein function is unknown (PubMed, May 2026).
ERBB3 L792V missense no effect - predicted ERBB3 (HER3) L792V lies within the protein kinase domain of the Erbb3 (Her3) protein (PMID: 29963236). L792V results in cell proliferation levels similar to wild-type Erbb3 (Her3) in culture (PMID: 29963236), and therefore, is predicted to have no effect on Erbb3 (Her3) protein function.
ERBB3 N126K missense unknown ERBB3 (HER3) N126K lies within the extracellular domain of the Erbb3 (Her3) protein (UniProt.org). N126K has been identified in the scientific literature (PMID: 29963236, PMID: 27602491, PMID: 32632529), but has not been biochemically characterized and therefore, its effect on Erbb3 (Her3) protein function is unknown (PubMed, Jun 2026).
ERBB3 P1142H missense unknown ERBB3 (HER3) P1142H lies within the cytoplasmic domain of the Erbb3 (Her3) protein (UniProt.org). P1142H has been identified in the scientific literature (PMID: 29963236, PMID: 24755471), but has not been biochemically characterized and therefore, its effect on Erbb3 (Her3) protein function is unknown (PubMed, Jun 2026).
ERBB3 R667H missense unknown ERBB3 (HER3) R667H lies within the cytoplasmic domain of the Erbb3 (Her3) protein (UniProt.org). R667H has been identified in the scientific literature (PMID: 29963236, PMID: 29420467, PMID: 29718453), but has not been biochemically characterized and therefore, its effect on Erbb3 (Her3) protein function is unknown (PubMed, Jun 2026).
ERBB3 T355I missense gain of function ERBB3 (HER3) T355I lies within the extracellular domain of the Erbb3 (Her3) protein (UniProt.org). T355I confers a gain of function to the Erbb3 (Her3) protein as demonstrated by increased proliferation of ER-positive cells as compared to wild-type ERBB3 (HER3), increased phosphorylation of downstream signaling molecules, and activation of the MAPK pathway in culture (PMID: 29963236).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB3 T355I estrogen-receptor positive breast cancer no benefit Fulvestrant Preclinical - Cell culture Actionable In a preclinical study, treatment with Faslodex (fulvestrant) did not significantly reduce cell proliferation of estrogen-receptor positive breast cancer cells expressing ERBB3 (HER3) T355I in culture relative to control and combination treatments (PMID: 29963236). 29963236
ERBB3 T355I estrogen-receptor positive breast cancer no benefit Lapatinib + SCH772984 Preclinical - Cell culture Actionable In a preclinical study, the combination of Tykerb (lapatinib) and SCH772984 resulted in a synergistic effect, demonstrating decreased colony formation and reduced cell proliferation, but to a lesser degree than Tykerb (lapatinib) combined with Faslodex (fulvestrant) in estrogen-receptor positive breast cancer cells expressing ERBB3 (HER3) T355I in culture (PMID: 29963236). 29963236
ERBB3 T355I estrogen-receptor positive breast cancer sensitive Fulvestrant + Lapatinib Preclinical - Cell culture Actionable In a preclinical study, the combination therapy of Faslodex (fulvestrant) and Tykerb (lapatinib) resulted in a synergistic effect, demonstrating decreased cell proliferation and reduced colony formation of estrogen-receptor positive breast cancer cells expressing ERBB3 (HER3) T355I in culture (PMID: 29963236). 29963236
ERBB3 T355I estrogen-receptor positive breast cancer no benefit SCH772984 Preclinical - Cell culture Actionable In a preclinical study, treatment with SCH772984 did not significantly reduce the proliferation of estrogen-receptor positive breast cancer cells expressing ERBB3 (HER3) T355I in culture relative to control and combination treatments (PMID: 29963236). 29963236
ERBB3 T355I estrogen-receptor positive breast cancer no benefit Lapatinib Preclinical - Cell culture Actionable In a preclinical study, treatment with Tykerb (lapatinib) did not significantly reduce the proliferation of estrogen-receptor positive breast cancer cells expressing ERBB3 (HER3) T355I in culture relative to control and combination treatments (PMID: 29963236). 29963236