The HER2 amplicon includes several genes required for the growth and survival of HER2 positive breast cancer cells

Kristine Kleivi Sahlberg, Vesa Hongisto, H. Edgren, Rami Mäkelä, Kirsi Hellström, Eldri U. Due, Hans Kristian Moen Vollan, Niko Sahlberg, M. Wolf, A.-L. Børresen-Dale, Merja Perälä, Olli Kallioniemi

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Abstract

Introduction; 20 % of breast cancers amplify and overexpress the HER2 oncogene. Regardless of the proven efficacy of HER2 inhibitor Trastuzumab, most of the patients respond poorly or become resistant to the treatment. Since the HER2 amplicon at 17q12-21 contains multiple genes, we wanted to explore the role of the HER2 co-amplified genes in breast cancer. Methods; We integrated data on the HER2 amplicon size from 71 HER2+ tumors and 10 cell lines with functional RNAi analysis of 23 core amplicon genes with several phenotypic endpoints in Trastuzumab responding and non-responding HER2+ breast cancer cells. Results; Silencing of HER2 caused a greater growth arrest in the responding compared to the non-responding cell lines, indicating that the resistant cells are inherently less dependent on the HER2 pathway. Several co-amplified genes also had growth inhibitory effects when silenced, indicating that they are needed to sustain the growth of breast cancer cells. Importantly, co-silencing of the PPP1R1B, STARD3 and PERLD1 together with HER2 led to a synergistic inhibition of cell viability as well as AKT and S6K phosphorylation. Conclusions; These results indicate that breast cancer cells become addicted to the amplification of several genes in the HER2 amplicon and that simultaneous targeting of these genes may be therapeutically beneficial. The observed synergistic effects seem to culminate to the PI3K-AKT complex, supporting the ongoing efforts to develop inhibitors for these pathways for combinatorial treatment of HER2+ breast cancers.
Original languageEnglish
Pages (from-to)392-401
JournalMolecular Oncology
Volume7
Issue number3
DOIs
Publication statusPublished - 2013
MoE publication typeA1 Journal article-refereed

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Breast Neoplasms
Survival
Growth
Genes
erbB-2 Genes
Gene Targeting
Gene Amplification
RNA Interference
Tumor Cell Line
Phosphatidylinositol 3-Kinases
Oncogenes
Cell Survival
Phosphorylation
Cell Line
Therapeutics
Trastuzumab

Cite this

Kleivi Sahlberg, K., Hongisto, V., Edgren, H., Mäkelä, R., Hellström, K., Due, E. U., ... Kallioniemi, O. (2013). The HER2 amplicon includes several genes required for the growth and survival of HER2 positive breast cancer cells. Molecular Oncology, 7(3), 392-401. https://doi.org/10.1016/j.molonc.2012.10.012
Kleivi Sahlberg, Kristine ; Hongisto, Vesa ; Edgren, H. ; Mäkelä, Rami ; Hellström, Kirsi ; Due, Eldri U. ; Moen Vollan, Hans Kristian ; Sahlberg, Niko ; Wolf, M. ; Børresen-Dale, A.-L. ; Perälä, Merja ; Kallioniemi, Olli. / The HER2 amplicon includes several genes required for the growth and survival of HER2 positive breast cancer cells. In: Molecular Oncology. 2013 ; Vol. 7, No. 3. pp. 392-401.
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abstract = "Introduction; 20 {\%} of breast cancers amplify and overexpress the HER2 oncogene. Regardless of the proven efficacy of HER2 inhibitor Trastuzumab, most of the patients respond poorly or become resistant to the treatment. Since the HER2 amplicon at 17q12-21 contains multiple genes, we wanted to explore the role of the HER2 co-amplified genes in breast cancer. Methods; We integrated data on the HER2 amplicon size from 71 HER2+ tumors and 10 cell lines with functional RNAi analysis of 23 core amplicon genes with several phenotypic endpoints in Trastuzumab responding and non-responding HER2+ breast cancer cells. Results; Silencing of HER2 caused a greater growth arrest in the responding compared to the non-responding cell lines, indicating that the resistant cells are inherently less dependent on the HER2 pathway. Several co-amplified genes also had growth inhibitory effects when silenced, indicating that they are needed to sustain the growth of breast cancer cells. Importantly, co-silencing of the PPP1R1B, STARD3 and PERLD1 together with HER2 led to a synergistic inhibition of cell viability as well as AKT and S6K phosphorylation. Conclusions; These results indicate that breast cancer cells become addicted to the amplification of several genes in the HER2 amplicon and that simultaneous targeting of these genes may be therapeutically beneficial. The observed synergistic effects seem to culminate to the PI3K-AKT complex, supporting the ongoing efforts to develop inhibitors for these pathways for combinatorial treatment of HER2+ breast cancers.",
author = "{Kleivi Sahlberg}, Kristine and Vesa Hongisto and H. Edgren and Rami M{\"a}kel{\"a} and Kirsi Hellstr{\"o}m and Due, {Eldri U.} and {Moen Vollan}, {Hans Kristian} and Niko Sahlberg and M. Wolf and A.-L. B{\o}rresen-Dale and Merja Per{\"a}l{\"a} and Olli Kallioniemi",
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Kleivi Sahlberg, K, Hongisto, V, Edgren, H, Mäkelä, R, Hellström, K, Due, EU, Moen Vollan, HK, Sahlberg, N, Wolf, M, Børresen-Dale, A-L, Perälä, M & Kallioniemi, O 2013, 'The HER2 amplicon includes several genes required for the growth and survival of HER2 positive breast cancer cells', Molecular Oncology, vol. 7, no. 3, pp. 392-401. https://doi.org/10.1016/j.molonc.2012.10.012

The HER2 amplicon includes several genes required for the growth and survival of HER2 positive breast cancer cells. / Kleivi Sahlberg, Kristine; Hongisto, Vesa; Edgren, H.; Mäkelä, Rami; Hellström, Kirsi; Due, Eldri U.; Moen Vollan, Hans Kristian; Sahlberg, Niko; Wolf, M.; Børresen-Dale, A.-L.; Perälä, Merja; Kallioniemi, Olli.

In: Molecular Oncology, Vol. 7, No. 3, 2013, p. 392-401.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - The HER2 amplicon includes several genes required for the growth and survival of HER2 positive breast cancer cells

AU - Kleivi Sahlberg, Kristine

AU - Hongisto, Vesa

AU - Edgren, H.

AU - Mäkelä, Rami

AU - Hellström, Kirsi

AU - Due, Eldri U.

AU - Moen Vollan, Hans Kristian

AU - Sahlberg, Niko

AU - Wolf, M.

AU - Børresen-Dale, A.-L.

AU - Perälä, Merja

AU - Kallioniemi, Olli

N1 - Project code: 73672

PY - 2013

Y1 - 2013

N2 - Introduction; 20 % of breast cancers amplify and overexpress the HER2 oncogene. Regardless of the proven efficacy of HER2 inhibitor Trastuzumab, most of the patients respond poorly or become resistant to the treatment. Since the HER2 amplicon at 17q12-21 contains multiple genes, we wanted to explore the role of the HER2 co-amplified genes in breast cancer. Methods; We integrated data on the HER2 amplicon size from 71 HER2+ tumors and 10 cell lines with functional RNAi analysis of 23 core amplicon genes with several phenotypic endpoints in Trastuzumab responding and non-responding HER2+ breast cancer cells. Results; Silencing of HER2 caused a greater growth arrest in the responding compared to the non-responding cell lines, indicating that the resistant cells are inherently less dependent on the HER2 pathway. Several co-amplified genes also had growth inhibitory effects when silenced, indicating that they are needed to sustain the growth of breast cancer cells. Importantly, co-silencing of the PPP1R1B, STARD3 and PERLD1 together with HER2 led to a synergistic inhibition of cell viability as well as AKT and S6K phosphorylation. Conclusions; These results indicate that breast cancer cells become addicted to the amplification of several genes in the HER2 amplicon and that simultaneous targeting of these genes may be therapeutically beneficial. The observed synergistic effects seem to culminate to the PI3K-AKT complex, supporting the ongoing efforts to develop inhibitors for these pathways for combinatorial treatment of HER2+ breast cancers.

AB - Introduction; 20 % of breast cancers amplify and overexpress the HER2 oncogene. Regardless of the proven efficacy of HER2 inhibitor Trastuzumab, most of the patients respond poorly or become resistant to the treatment. Since the HER2 amplicon at 17q12-21 contains multiple genes, we wanted to explore the role of the HER2 co-amplified genes in breast cancer. Methods; We integrated data on the HER2 amplicon size from 71 HER2+ tumors and 10 cell lines with functional RNAi analysis of 23 core amplicon genes with several phenotypic endpoints in Trastuzumab responding and non-responding HER2+ breast cancer cells. Results; Silencing of HER2 caused a greater growth arrest in the responding compared to the non-responding cell lines, indicating that the resistant cells are inherently less dependent on the HER2 pathway. Several co-amplified genes also had growth inhibitory effects when silenced, indicating that they are needed to sustain the growth of breast cancer cells. Importantly, co-silencing of the PPP1R1B, STARD3 and PERLD1 together with HER2 led to a synergistic inhibition of cell viability as well as AKT and S6K phosphorylation. Conclusions; These results indicate that breast cancer cells become addicted to the amplification of several genes in the HER2 amplicon and that simultaneous targeting of these genes may be therapeutically beneficial. The observed synergistic effects seem to culminate to the PI3K-AKT complex, supporting the ongoing efforts to develop inhibitors for these pathways for combinatorial treatment of HER2+ breast cancers.

U2 - 10.1016/j.molonc.2012.10.012

DO - 10.1016/j.molonc.2012.10.012

M3 - Article

VL - 7

SP - 392

EP - 401

JO - Molecular Oncology

JF - Molecular Oncology

SN - 1574-7891

IS - 3

ER -