Lapatinib Restores Hormone Sensitivity with Differential Effects on Estrogen Receptor Signaling in Cell Models of Human Epidermal Growth Factor Receptor 2–Negative Breast Cancer with Acquired Endocrine Resistance

Leary, Alexandra; Drury, Suzanne; Detre, Simone; Pancholi, Sunil; Lykkesfeldt, Annè E.; Martin, Lesley-Ann; Dowsett, Mitch; Johnston, Stephen

doi:10.1158/1078-0432.ccr-09-1764

Cited by 81 publications

(63 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Downregulation of RET re-sensitized TAM R -1 cells to the anti-proliferative effects of 4-OHtamoxifen. Interestingly, TAM R -1 cells also show elevated level of phosphorylated ErbB2 and the magnitude of re-sensitization to tamoxifen in the RET siRNA-treated cells was equivalent to that previously reported for the ErbB2 inhibitors AG825 and lapatanib (Pancholi et al, 2008;Leary et al, 2010). Consequently, these data presented here provide evidence that RET is Figure 3 RET signaling induces ERa Ser118 and Ser167 phosphorylation through mTOR.…”

Section: Discussionsupporting

confidence: 85%

Targeting the receptor tyrosine kinase RET sensitizes breast cancer cells to tamoxifen treatment and reveals a role for RET in endocrine resistance

et al. 2010

View full text Add to dashboard Cite

Endocrine therapy is the main therapeutic option for patients with estrogen receptor (ERa)-positive breast cancer. Resistance to this treatment is often associated with estrogen-independent activation of ERa. In this study, we show that in ERa-positive breast cancer cells, activation of the receptor tyrosine kinase RET (REarranged during Transfection) by its ligand GDNF results in increased ERa phosphorylation on Ser118 and Ser167 and estrogen-independent activation of ERa transcriptional activity. Further, we identify mTOR as a key component in this downstream signaling pathway. In tamoxifen response experiments, RET downregulation resulted in 6.2-fold increase in sensitivity of MCF7 cells to antiproliferative effects of tamoxifen, whereas GDNF stimulation had a protective effect against the drug. In tamoxifen-resistant (TAM R -1) MCF7 cells, targeting RET restored tamoxifen sensitivity. Finally, examination of two independent tissue microarrays of primary human breast cancers revealed that expression of RET protein was significantly associated with ERa-positive tumors and that in primary tumors from patients who subsequently developed invasive recurrence after adjuvant tamoxifen treatment, there was a twofold increase in the number of RET-positive tumors. Together these findings identify RET as a potentially important therapeutic target in ERa-positive breast cancers and in particular in tamoxifen-resistant tumors.

show abstract

Section: Discussionsupporting

confidence: 85%

Targeting the receptor tyrosine kinase RET sensitizes breast cancer cells to tamoxifen treatment and reveals a role for RET in endocrine resistance

et al. 2010

View full text Add to dashboard Cite

show abstract

“…In fact, lapatinib was recently shown to restore endocrine sensitivity in breast cancer cells with acquired resistance because of modest adaptive upregulation of HER2 (Leary et al, 2010). Moreover, lack of p53 and phosphorylated HER3 have been associated with better lapatinib responses in HER2-overexpressing patients; HER2-overexpressing tumors also exhibit increased expression of heregulin/ neuregulin (Johnston et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Breast tumor progression induced by loss of BTG2 expression is inhibited by targeted therapy with the ErbB/HER inhibitor lapatinib

et al. 2011

View full text Add to dashboard Cite

The B-cell translocation gene-2 (BTG2), a p53-inducible gene, is suppressed in mammary epithelial cells during gestation and lactation. In human breast cancer, decreased BTG2 expression correlates with high tumor grade and size, p53 status, blood and lymph vessel invasion, local and metastatic recurrence and decrease in overall survival, suggesting that suppression of BTG2 has a critical role in disease progression. To analyze the role of BTG2 in breast cancer progression, BTG2 expression was knocked down in mammary epithelial cells. Suppression of BTG2 enhances the motility of cells in vitro and tumor growth and metastasis in vivo. The effects of BTG2 knockdown are mediated through stabilization of the human epidermal growth factor receptor (HER) ligands neuregulin and epiregulin and activation of the HER2 and HER3 receptors, leading to elevated AKT phosphorylation. Suppression of HER activation using the tyrosine kinase inhibitor lapatinib abrogates the effects of BTG2 knockdown, including the increased cell migration observed in vitro and the enhancement of tumorigenesis and metastasis in vivo. These results link BTG2-dependent effects on tumor progression to ErbB receptor signaling, and raise the possibility that targeted inhibition of this pathway may be relevant in the treatment of breast cancers that have reduced BTG2 expression.

show abstract

“…These findings might reflect acquired resistance to tamoxifen treatment in the adjuvant setting of HR positive BC patients. It has been recently reported that acquired endocrine resistance in positive ER/negative HER2 BC may be associated with an adaptive increase in HER2, although exactly how aberrant HER2 signaling affects the ERa pathway is poorly understood (27). The discordance between PBC and MBC reported in our series resembles other retrospective and prospective studies PAFAHIB1 PMP22 TOM1L2 WSB1 WSB1 WSB1 NOS2A TRAF4 CPD RNF135 PEX12 NEUROD2 ER882 ER882 ER882 RARA TOP2A TOP2A TOP2A BRCA1 BRCA1 SGCA GH1 METRNL PAFAHIB1 PMP22 TOM1L2 WSB1 NOS2A TRAF4 CPD RNF135 PEX12 NEUROD2 HER2 RARA TOP2A BRCA1 SGCA GH1 METERNL 14 12 10 8 6 4 2 0 Ratio PAFAHIB1 PMP22 TOM1L2 WSB1 WSB1 WSB1 NOS2A TRAF4 CPD RNF135 PEX12 NEUROD2 ER882 ER882 ER882 RARA TOP2A TOP2A TOP2A BRCA1 BRCA1 SGCA GH1 9,12,14,28).…”

Section: Discussionmentioning

confidence: 99%

HER2 Protein and Gene Variation between Primary and Metastatic Breast Cancer: Significance and Impact on Patient Care

Fabi¹,

Benedetto²,

Metro³

et al. 2011

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: To analyze HER2 status in primary breast cancer (PBC) compared with correspondent metachronous metastases and to investigate whether BC phenotype may be predictive of change in HER2 expression.Experimental Design: HER2 was investigated by immunohistochemistry, silver in situ hybridization (SISH), and FISH, in a series of 137 tumors, building up a tissue microarray to concurrently analyze each single PBC and metastatic (MBC) on the same slide.Results: HER2 status was discordant in 14 cases (10%): 12 negative in PBC and positive in metastases and two positive in PBC and negative in metastases (P ¼ 0.04). These findings were confirmed by a PCR based test termed Multiplex Ligation-dependent Probe Amplification (MLPA). HER2 status changed in hormone receptor-positive BC more frequently than in negative ones (P ¼ 0.002). In addition, we evaluated HER2 gene and chromosome 17 copy number by SISH in the 123 cases with unchanged HER2 status during progression. We found consistent HER2 gene copy number stability in the 100 nonamplified cases. Conversely, of the 23 amplified PBC, 13 (57%) demonstrated a significant increase in the HER2 gene and chromosome 17 copy number in their paired metastases (P ¼ 0.01), as defined by SISH (k ¼ 0.54, P < 0.0001) and MLPA. Patients who changed HER2 status from negative to positive, presented significant longer time to progression when treated with trastuzumab compared to those who were untreated (P ¼ 0.04).Conclusions: When feasible, HER2 reassessment in metastatic lesions should be carefully taken into account, especially for metastases coming from primary hormone receptor-positive BC.

show abstract

Lapatinib Restores Hormone Sensitivity with Differential Effects on Estrogen Receptor Signaling in Cell Models of Human Epidermal Growth Factor Receptor 2–Negative Breast Cancer with Acquired Endocrine Resistance

Cited by 81 publications

References 33 publications

Targeting the receptor tyrosine kinase RET sensitizes breast cancer cells to tamoxifen treatment and reveals a role for RET in endocrine resistance

Targeting the receptor tyrosine kinase RET sensitizes breast cancer cells to tamoxifen treatment and reveals a role for RET in endocrine resistance

Breast tumor progression induced by loss of BTG2 expression is inhibited by targeted therapy with the ErbB/HER inhibitor lapatinib

HER2 Protein and Gene Variation between Primary and Metastatic Breast Cancer: Significance and Impact on Patient Care

Contact Info

Product

Resources

About