VOLUME
32
䡠
NUMBER
10
䡠
APRIL
1
2014
JOURNAL OF CLINICAL ONCOLOGY
UNDERSTANDING THE PATHWAY
Estrogen Receptor and Receptor Tyrosine Kinase Signaling: Use of Combinatorial Hormone and Epidermal Growth Factor Receptor/Human Epidermal Growth Factor Receptor 2–Targeted Therapies for Breast Cancer Daniel J. Zabransky and Ben Ho Park, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD See accompanying article on page 1050
Estrogen receptor ␣ (ER␣) is expressed in nearly 70% of breast cancers and is a key driver of growth in ER-positive breast tumors. ER is primarily a nuclear protein that, when activated by estrogens, acts as a ligand-dependent transcription factor and promotes the expression of several genes that enhance cell survival, proliferation, and tumor progression1,2 (Fig 1). Examples of gene products upregulated by ER’s genomic actions include Bcl-2, cyclin D1, and the insulin-like growth factor 1 (IGF-1) receptor.3,4 Activated ER can also be localized to the cellular membrane and exert rapid, nongenomic effects. Here ER can colocalize with numerous different signaling molecules that lead to activation of growth and survival-promoting pathways, including the mitogen-activated protein kinase (MAPK) and Akt pathways.5 The use of hormone therapies, including aromatase inhibitors and selective estrogen receptor modulators, that target and downregulate ER signaling in the breast is a mainstay of treatment for patients with ER-positive breast cancers. Although these agents are extremely effective, a significant proportion of patients exhibit de novo or acquired resistance to hormone therapy.6,7 A proposed mechanism of resistance to hormone therapy is signaling crosstalk between ER and growth factor receptor tyrosine kinases (RTKs).8-10 In an accompanying article, Guarneri et al11 report the results of a randomized, double-blind, placebo-controlled, multicenter phase IIb neoadjuvant study of the aromatase inhibitor letrozole combined with the dual epidermal growth factor receptor/human epidermal growth factor receptor 2 (EGFR/ HER2) inhibitor lapatinib in postmenopausal hormone receptor– positive, HER2-negative early-stage breast cancer. Their results show that clinical response rates were similar for patients who received a combination of letrozole and lapatinib compared with patients receiving letrozole and placebo (70% v 63%, respectively). However, on further subset analysis, they found that patients with a PIK3CA mutation (37%) had a significantly higher likelihood of clinical response to the letrozole-lapatinib combination therapy versus those patients without PIK3CA mutations (overall response 1084
© 2014 by American Society of Clinical Oncology
rate of 93% for patients with mutant PIK3CA v 63% for patients with wild-type PIK3CA). PIK3CA is the gene that encodes the PI3K catalytic subunit p110␣, and the PI3K pathway is the most commonly mutated pathway in breast cancers, with PIK3CA recurrent hotspot mutations found at high frequency in ER-positive breast tumors.12,13 PI3K has been implicated as a key mediator of hormone resistance in preclinical models, and evidence suggests that hyperactivation of PI3K may enhance estrogen-independent and -dependent ER transcriptional activity.14 Although inhibition of the PI3K pathway has been postulated to sensitize cells to hormone therapy, several retrospective clinical studies have shown that activating mutations in PIK3CA paradoxically predict for a better long-term prognosis in patients with ER-positive breast cancers treated with hormonal therapy15 although other studies have shown contradictory results.16 It is known that activated RTKs and their downstream signaling partners can directly interact with ER and cause phosphorylation of key residues in the AF-1 domain of ER. This phosphorylation results in activation of ER in a ligand-independent fashion to promote cell growth and survival.17 In addition, membrane-activated ER can activate the EGFR pathway by increasing the production of the EGFR ligand heparin-binding epidermal growth factor.3 Furthermore, in vitro studies have shown that breast cancer cell lines with acquired resistance to hormone therapy have increased expression and activation of EGFR and HER2 along with their downstream signaling pathways.18 The use of ErbB-targeted tyrosine kinase inhibitors or the anti-HER2 monoclonal antibody trastuzumab significantly inhibits the growth of these cells after development of resistance to hormone therapies.19 In addition, sensitivity to hormone therapies can be restored when resistant cells are treated with lapatinib, a dual EGFR/ HER2 inhibitor.20 Together, these data suggest that enhanced RTK signaling and activationofPI3Ksignalingmaybekeycontributorstoresistancetohormone therapies in breast cancer. This provides the rationale for the dual Journal of Clinical Oncology, Vol 32, No 10 (April 1), 2014: pp 1084-1086
Information downloaded from jco.ascopubs.org and provided by at UCSF LIBRARY & CKM on October 4, 2014 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 169.230.243.252
Combinatorial Hormone and Targeted Therapies for Breast Cancer
GF
Hb-EGF
Receptor tyrosine kinase
E2
E2
Mutated in approximately 30% of breast cancers
MMPs ER
E2 E2
Src
PIP3
}
ER
PIP2
p85 p110α PI3K PTEN
RAS E2
E2
AKT-independent effects of mutant PI3K
MAPK/ERK Pathway ER
ER
E2 E2
E2
ER
ER
PDK1
Phosphorylation of transcription factors potentiate their effects on transcription in the nucleus
AKT mTOR
Tumor proliferation Transcription and survival
E2 E2
E2
ER
ER
Fig 1. Estrogen receptor ␣ (ER␣) and growth factor receptor signaling pathways. Estrogens such as estradiol (E2) can bind to either nuclear or membrane ER. When estrogen binds nuclear ER, ERs dimerize and translocate to the nucleus and act as transcription factors. Binding of estrogens to membrane-localized ER activates Src, which then activates matrix metalloproteinases (MMPs) to cleave heparin-binding epidermal growth factor (Hb-EGF). Hb-EGF is released from the cell membrane and is an epidermal growth factor receptor (EGFR) ligand. Growth factor receptor tyrosine kinases, including those in the ErbB family, are activated when specific growth factor (GF) ligands bind to their extracellular domains. Ligand binding induces a conformation change, which induces receptor dimerization and autophosphorylation of tyrosine kinase residues in the intracellular domain of the receptors. These phosphorylated residues act as binding sites for adapter proteins which lead to activation of signal transduction pathways including the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) and Ras/mitogen-activated protein kinase (MAPK)/ERK pathways, PI3K comprising the p85 regulatory and the p110␣ catalytic subunits phosphorylates phosphatidylinositol (4,5)-bisphosphate (PIP2) to phosphatidylinositol (3,4,5)-triphosphate (PIP3). This process is regulated by the tumor suppressor PTEN. PIP3 then activates downstream proteins, including PDK1 and Akt. When PIK3CA is mutated, resulting in a mutated p110␣ PI3K subunit, PI3K can exert Akt-independent signaling effects (dashed arrow). GF receptor signaling pathways potentiate the effects of transcription factors, including ER, to enhance cellular proliferation, growth, and survival.
inhibition strategy of Guarneri et al,11 but like most good studies, their results challenge our current understanding of the interplay between RTKs and PIK3CA mutations. Specifically, the results of their subset analyses examining PIK3CA mutation status and response are surprising in that inhibition of EGFR/HER2, an upstream component in the PI3K signaling pathway, had a higher likelihood of clinical response for patients that harbored a PIK3CA mutation. This is somewhat unexpected because mutation of PIK3CA might be predicted to stimulate the PI3K pathway at a nodal point distal to RTK activation (Fig 1). Thus, this finding at first glance appears to be paradoxical, because one might have hypothesized that PIK3CA mutations would lead to a resistance phenotype when using EGFR/HER2 inhibitors, similar to the situation with mutant KRAS predicting for resistance to EGFR antibody inhibitors. However, prior preclinical work has indicated that mutant PIK3CA may have direct effects on RTK signaling at the receptor-ligand level, especially HER2 signaling.21 For example, expression of the ErbB receptor ligands heregulin and epiregulin was significantly increased in HER2overexpressing human mammary epithelium cells in which an H1047R (exon 20) PIK3CA hotspot mutation was introduced. In addition, the HER3 receptor was found to be highly activated www.jco.org
and phosphorylated in these PIK3CA mutant cells. This activation of ErbB family signaling by mutant PIK3CA may lead to positive feedback on the PI3K pathway and activation of other important promoters of cell growth and survival including the MAPK, signal transducer and activator of transcription (STAT), PKC, and PLC-␥ pathways.22,23 Furthermore, oncogenic mutations in PIK3CA might lead to a rewiring of traditional signal transduction pathways. For instance, it has been demonstrated that in certain cancer cell lines, mutant PIK3CA can exert transformative effects through an Akt-independent mechanism.24 This finding might also explain why activating PIK3CA mutations may not be resistant to RTK inhibition in certain cases, since these cancers may require dysregulation of the upstream signaling pathway that leads to activation of Akt independent of PI3K activity. Therefore, inhibition of ErbB RTKs in the context of activating PIK3CA mutations may serve as a viable strategy to downregulate aberrant RTK signaling and restore sensitivity to hormone therapies in patients with ERpositive breast cancer. Further work at both the bench and bedside will help illuminate how mutant PIK3CA usurps normal RTK function leading to rewiring of pathways that may prove to be future targets for therapy. © 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at UCSF LIBRARY & CKM on October 4, 2014 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 169.230.243.252
1085
Zabransky and Park
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES 1. Osborne CK, Schiff R: Estrogen-receptor biology: Continuing progress and therapeutic implications. J Clin Oncol 23:1616-1622, 2005 2. Shao W, Brown M: Advances in estrogen receptor biology: Prospects for improvements in targeted breast cancer therapy. Breast Cancer Res 6:39-52, 2004 3. Arpino G, Wiechmann L, Osborne CK, et al: Crosstalk between the estrogen receptor and the HER tyrosine kinase receptor family: Molecular mechanism and clinical implications for endocrine therapy resistance. Endocr Rev 29:217-233, 2008 4. Klinge CM, Jernigan SC, Smith SL, et al: Estrogen response element sequence impacts the conformation and transcriptional activity of estrogen receptor alpha. Mol Cell Endocrinol 174:151-166, 2001 5. Song RX: Membrane-initiated steroid signaling action of estrogen and breast cancer. Semin Reprod Med 25:187-197, 2007 6. Clark GM, Osborne CK, McGuire WL: Correlations between estrogen receptor, progesterone receptor, and patient characteristics in human breast cancer. J Clin Oncol 2:1102-1109, 1984 7. Fu X, Osborne CK, Schiff R: Biology and therapeutic potential of PI3K signaling in ER⫹/ HER2-negative breast cancer. Breast 22:S12-S18, 2013 8. Pancholi S, Lykkesfeldt AE, Hilmi C, et al: ERBB2 influences the subcellular localization of the estrogen receptor in tamoxifen-resistant MCF-7 cells leading to the activation of AKT and RPS6KA2. Endocr Relat Cancer 15:985-1002, 2008 9. Martin LA, Farmer I, Johnston SR, et al: Enhanced estrogen receptor (ER) alpha, ERBB2, and MAPK signal transduction pathways operate during
AUTHOR CONTRIBUTIONS Manuscript writing: All authors Final approval of manuscript: All authors
the adaptation of MCF-7 cells to long term estrogen deprivation. J Biol Chem 278:30458-30468, 2003 10. Knowlden JM, Hutcheson IR, Jones HE, et al: Elevated levels of epidermal growth factor receptor/ c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 Cells. Endocrinology 144:1032-1044, 2003 11. Guarneri V, Generali DG, Frassoldati A, et al: Double-blind, placebo-controlled, multicenter randomized phase IIB neoadjuvant study of letrozole-lapatinib in postmenopausal hormone receptor–positive, human epidermal growth factor receptor–negative, operable breast cancer. J Clin Oncol 32:1050-1057, 2014 12. Bachman KE, Argani P, Samuels Y, et al: The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther 3:772-775, 2004 13. Karakas B, Bachman KE, Park BH: Mutation of the PIK3CA oncogene in human cancers. Br J Cancer 94:455-459, 2006 14. Miller TW, Balko JM, Arteaga CL: Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J Clin Oncol 29:4452-4461, 2011 15. Ellis MJ, Lin L, Crowder R, et al: Phosphatidylinositol-3-kinase alpha catalytic subunit mutation and response to neoadjuvant endocrine therapy for estrogen receptor positive breast cancer. Breast Cancer Res Treat 119:379-390, 2010 16. Barbareschi M, Buttitta F, Felicioni L, et al: Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas. Clin Cancer Res 13:60646069, 2007 17. Schiff R, Massarweh S, Shou J, et al: Breast cancer endocrine resistance: How growth factor signaling and estrogen receptor coregulators modulate response. Clin Cancer Res 9:447S-454S, 2003 18. Gutierrez MC, Detre S, Johnston S, et al: Molecular changes in tamoxifen-resistant breast
cancer: Relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase. J Clin Oncol 23:2469-2476, 2005 19. Gee JM, Harper ME, Hutcheson IR, et al: The antiepidermal growth factor receptor agent gefitinib (ZD1839/Iressa) improves antihormone response and prevents development of resistance in breast cancer in vitro. Endocrinology 144:51055117, 2003 20. Leary AF, Drury S, Detre S, et al: 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. Clin Cancer Res 16:1486-1497, 2010 21. Chakrabarty A, Rexer BN, Wang SE, et al: H1047R phosphatidylinositol 3-kinase mutant enhances HER2-mediated transformation by heregulin production and activation of HER3. Oncogene 29: 5193-5203, 2010 22. Hurvitz SA, Hu Y, O’Brien N, et al: Current approaches and future directions in the treatment of HER2-positive breast cancer. Cancer Treat Rev 39: 219-229, 2013 23. Laurent-Puig P, Manceau G, Zucman-Rossi J, et al: Dual blockade of epidermal growth factor receptor-induced pathways: A new avenue to treat metastatic colorectal cancer. J Clin Oncol 30:15501552, 2012 24. Vasudevan KM, Barbie DA, Davies MA, et al: AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell 16:21-32, 2009
DOI: 10.1200/JCO.2013.53.5070; published online ahead of print at www.jco.org on March 3, 2014
■ ■ ■
1086
© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at UCSF LIBRARY & CKM on October 4, 2014 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 169.230.243.252
32
䡠
NUMBER
10
䡠
APRIL
1
2014
JOURNAL OF CLINICAL ONCOLOGY
UNDERSTANDING THE PATHWAY
Estrogen Receptor and Receptor Tyrosine Kinase Signaling: Use of Combinatorial Hormone and Epidermal Growth Factor Receptor/Human Epidermal Growth Factor Receptor 2–Targeted Therapies for Breast Cancer Daniel J. Zabransky and Ben Ho Park, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD See accompanying article on page 1050
Estrogen receptor ␣ (ER␣) is expressed in nearly 70% of breast cancers and is a key driver of growth in ER-positive breast tumors. ER is primarily a nuclear protein that, when activated by estrogens, acts as a ligand-dependent transcription factor and promotes the expression of several genes that enhance cell survival, proliferation, and tumor progression1,2 (Fig 1). Examples of gene products upregulated by ER’s genomic actions include Bcl-2, cyclin D1, and the insulin-like growth factor 1 (IGF-1) receptor.3,4 Activated ER can also be localized to the cellular membrane and exert rapid, nongenomic effects. Here ER can colocalize with numerous different signaling molecules that lead to activation of growth and survival-promoting pathways, including the mitogen-activated protein kinase (MAPK) and Akt pathways.5 The use of hormone therapies, including aromatase inhibitors and selective estrogen receptor modulators, that target and downregulate ER signaling in the breast is a mainstay of treatment for patients with ER-positive breast cancers. Although these agents are extremely effective, a significant proportion of patients exhibit de novo or acquired resistance to hormone therapy.6,7 A proposed mechanism of resistance to hormone therapy is signaling crosstalk between ER and growth factor receptor tyrosine kinases (RTKs).8-10 In an accompanying article, Guarneri et al11 report the results of a randomized, double-blind, placebo-controlled, multicenter phase IIb neoadjuvant study of the aromatase inhibitor letrozole combined with the dual epidermal growth factor receptor/human epidermal growth factor receptor 2 (EGFR/ HER2) inhibitor lapatinib in postmenopausal hormone receptor– positive, HER2-negative early-stage breast cancer. Their results show that clinical response rates were similar for patients who received a combination of letrozole and lapatinib compared with patients receiving letrozole and placebo (70% v 63%, respectively). However, on further subset analysis, they found that patients with a PIK3CA mutation (37%) had a significantly higher likelihood of clinical response to the letrozole-lapatinib combination therapy versus those patients without PIK3CA mutations (overall response 1084
© 2014 by American Society of Clinical Oncology
rate of 93% for patients with mutant PIK3CA v 63% for patients with wild-type PIK3CA). PIK3CA is the gene that encodes the PI3K catalytic subunit p110␣, and the PI3K pathway is the most commonly mutated pathway in breast cancers, with PIK3CA recurrent hotspot mutations found at high frequency in ER-positive breast tumors.12,13 PI3K has been implicated as a key mediator of hormone resistance in preclinical models, and evidence suggests that hyperactivation of PI3K may enhance estrogen-independent and -dependent ER transcriptional activity.14 Although inhibition of the PI3K pathway has been postulated to sensitize cells to hormone therapy, several retrospective clinical studies have shown that activating mutations in PIK3CA paradoxically predict for a better long-term prognosis in patients with ER-positive breast cancers treated with hormonal therapy15 although other studies have shown contradictory results.16 It is known that activated RTKs and their downstream signaling partners can directly interact with ER and cause phosphorylation of key residues in the AF-1 domain of ER. This phosphorylation results in activation of ER in a ligand-independent fashion to promote cell growth and survival.17 In addition, membrane-activated ER can activate the EGFR pathway by increasing the production of the EGFR ligand heparin-binding epidermal growth factor.3 Furthermore, in vitro studies have shown that breast cancer cell lines with acquired resistance to hormone therapy have increased expression and activation of EGFR and HER2 along with their downstream signaling pathways.18 The use of ErbB-targeted tyrosine kinase inhibitors or the anti-HER2 monoclonal antibody trastuzumab significantly inhibits the growth of these cells after development of resistance to hormone therapies.19 In addition, sensitivity to hormone therapies can be restored when resistant cells are treated with lapatinib, a dual EGFR/ HER2 inhibitor.20 Together, these data suggest that enhanced RTK signaling and activationofPI3Ksignalingmaybekeycontributorstoresistancetohormone therapies in breast cancer. This provides the rationale for the dual Journal of Clinical Oncology, Vol 32, No 10 (April 1), 2014: pp 1084-1086
Information downloaded from jco.ascopubs.org and provided by at UCSF LIBRARY & CKM on October 4, 2014 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 169.230.243.252
Combinatorial Hormone and Targeted Therapies for Breast Cancer
GF
Hb-EGF
Receptor tyrosine kinase
E2
E2
Mutated in approximately 30% of breast cancers
MMPs ER
E2 E2
Src
PIP3
}
ER
PIP2
p85 p110α PI3K PTEN
RAS E2
E2
AKT-independent effects of mutant PI3K
MAPK/ERK Pathway ER
ER
E2 E2
E2
ER
ER
PDK1
Phosphorylation of transcription factors potentiate their effects on transcription in the nucleus
AKT mTOR
Tumor proliferation Transcription and survival
E2 E2
E2
ER
ER
Fig 1. Estrogen receptor ␣ (ER␣) and growth factor receptor signaling pathways. Estrogens such as estradiol (E2) can bind to either nuclear or membrane ER. When estrogen binds nuclear ER, ERs dimerize and translocate to the nucleus and act as transcription factors. Binding of estrogens to membrane-localized ER activates Src, which then activates matrix metalloproteinases (MMPs) to cleave heparin-binding epidermal growth factor (Hb-EGF). Hb-EGF is released from the cell membrane and is an epidermal growth factor receptor (EGFR) ligand. Growth factor receptor tyrosine kinases, including those in the ErbB family, are activated when specific growth factor (GF) ligands bind to their extracellular domains. Ligand binding induces a conformation change, which induces receptor dimerization and autophosphorylation of tyrosine kinase residues in the intracellular domain of the receptors. These phosphorylated residues act as binding sites for adapter proteins which lead to activation of signal transduction pathways including the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) and Ras/mitogen-activated protein kinase (MAPK)/ERK pathways, PI3K comprising the p85 regulatory and the p110␣ catalytic subunits phosphorylates phosphatidylinositol (4,5)-bisphosphate (PIP2) to phosphatidylinositol (3,4,5)-triphosphate (PIP3). This process is regulated by the tumor suppressor PTEN. PIP3 then activates downstream proteins, including PDK1 and Akt. When PIK3CA is mutated, resulting in a mutated p110␣ PI3K subunit, PI3K can exert Akt-independent signaling effects (dashed arrow). GF receptor signaling pathways potentiate the effects of transcription factors, including ER, to enhance cellular proliferation, growth, and survival.
inhibition strategy of Guarneri et al,11 but like most good studies, their results challenge our current understanding of the interplay between RTKs and PIK3CA mutations. Specifically, the results of their subset analyses examining PIK3CA mutation status and response are surprising in that inhibition of EGFR/HER2, an upstream component in the PI3K signaling pathway, had a higher likelihood of clinical response for patients that harbored a PIK3CA mutation. This is somewhat unexpected because mutation of PIK3CA might be predicted to stimulate the PI3K pathway at a nodal point distal to RTK activation (Fig 1). Thus, this finding at first glance appears to be paradoxical, because one might have hypothesized that PIK3CA mutations would lead to a resistance phenotype when using EGFR/HER2 inhibitors, similar to the situation with mutant KRAS predicting for resistance to EGFR antibody inhibitors. However, prior preclinical work has indicated that mutant PIK3CA may have direct effects on RTK signaling at the receptor-ligand level, especially HER2 signaling.21 For example, expression of the ErbB receptor ligands heregulin and epiregulin was significantly increased in HER2overexpressing human mammary epithelium cells in which an H1047R (exon 20) PIK3CA hotspot mutation was introduced. In addition, the HER3 receptor was found to be highly activated www.jco.org
and phosphorylated in these PIK3CA mutant cells. This activation of ErbB family signaling by mutant PIK3CA may lead to positive feedback on the PI3K pathway and activation of other important promoters of cell growth and survival including the MAPK, signal transducer and activator of transcription (STAT), PKC, and PLC-␥ pathways.22,23 Furthermore, oncogenic mutations in PIK3CA might lead to a rewiring of traditional signal transduction pathways. For instance, it has been demonstrated that in certain cancer cell lines, mutant PIK3CA can exert transformative effects through an Akt-independent mechanism.24 This finding might also explain why activating PIK3CA mutations may not be resistant to RTK inhibition in certain cases, since these cancers may require dysregulation of the upstream signaling pathway that leads to activation of Akt independent of PI3K activity. Therefore, inhibition of ErbB RTKs in the context of activating PIK3CA mutations may serve as a viable strategy to downregulate aberrant RTK signaling and restore sensitivity to hormone therapies in patients with ERpositive breast cancer. Further work at both the bench and bedside will help illuminate how mutant PIK3CA usurps normal RTK function leading to rewiring of pathways that may prove to be future targets for therapy. © 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at UCSF LIBRARY & CKM on October 4, 2014 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 169.230.243.252
1085
Zabransky and Park
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES 1. Osborne CK, Schiff R: Estrogen-receptor biology: Continuing progress and therapeutic implications. J Clin Oncol 23:1616-1622, 2005 2. Shao W, Brown M: Advances in estrogen receptor biology: Prospects for improvements in targeted breast cancer therapy. Breast Cancer Res 6:39-52, 2004 3. Arpino G, Wiechmann L, Osborne CK, et al: Crosstalk between the estrogen receptor and the HER tyrosine kinase receptor family: Molecular mechanism and clinical implications for endocrine therapy resistance. Endocr Rev 29:217-233, 2008 4. Klinge CM, Jernigan SC, Smith SL, et al: Estrogen response element sequence impacts the conformation and transcriptional activity of estrogen receptor alpha. Mol Cell Endocrinol 174:151-166, 2001 5. Song RX: Membrane-initiated steroid signaling action of estrogen and breast cancer. Semin Reprod Med 25:187-197, 2007 6. Clark GM, Osborne CK, McGuire WL: Correlations between estrogen receptor, progesterone receptor, and patient characteristics in human breast cancer. J Clin Oncol 2:1102-1109, 1984 7. Fu X, Osborne CK, Schiff R: Biology and therapeutic potential of PI3K signaling in ER⫹/ HER2-negative breast cancer. Breast 22:S12-S18, 2013 8. Pancholi S, Lykkesfeldt AE, Hilmi C, et al: ERBB2 influences the subcellular localization of the estrogen receptor in tamoxifen-resistant MCF-7 cells leading to the activation of AKT and RPS6KA2. Endocr Relat Cancer 15:985-1002, 2008 9. Martin LA, Farmer I, Johnston SR, et al: Enhanced estrogen receptor (ER) alpha, ERBB2, and MAPK signal transduction pathways operate during
AUTHOR CONTRIBUTIONS Manuscript writing: All authors Final approval of manuscript: All authors
the adaptation of MCF-7 cells to long term estrogen deprivation. J Biol Chem 278:30458-30468, 2003 10. Knowlden JM, Hutcheson IR, Jones HE, et al: Elevated levels of epidermal growth factor receptor/ c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 Cells. Endocrinology 144:1032-1044, 2003 11. Guarneri V, Generali DG, Frassoldati A, et al: Double-blind, placebo-controlled, multicenter randomized phase IIB neoadjuvant study of letrozole-lapatinib in postmenopausal hormone receptor–positive, human epidermal growth factor receptor–negative, operable breast cancer. J Clin Oncol 32:1050-1057, 2014 12. Bachman KE, Argani P, Samuels Y, et al: The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther 3:772-775, 2004 13. Karakas B, Bachman KE, Park BH: Mutation of the PIK3CA oncogene in human cancers. Br J Cancer 94:455-459, 2006 14. Miller TW, Balko JM, Arteaga CL: Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J Clin Oncol 29:4452-4461, 2011 15. Ellis MJ, Lin L, Crowder R, et al: Phosphatidylinositol-3-kinase alpha catalytic subunit mutation and response to neoadjuvant endocrine therapy for estrogen receptor positive breast cancer. Breast Cancer Res Treat 119:379-390, 2010 16. Barbareschi M, Buttitta F, Felicioni L, et al: Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas. Clin Cancer Res 13:60646069, 2007 17. Schiff R, Massarweh S, Shou J, et al: Breast cancer endocrine resistance: How growth factor signaling and estrogen receptor coregulators modulate response. Clin Cancer Res 9:447S-454S, 2003 18. Gutierrez MC, Detre S, Johnston S, et al: Molecular changes in tamoxifen-resistant breast
cancer: Relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase. J Clin Oncol 23:2469-2476, 2005 19. Gee JM, Harper ME, Hutcheson IR, et al: The antiepidermal growth factor receptor agent gefitinib (ZD1839/Iressa) improves antihormone response and prevents development of resistance in breast cancer in vitro. Endocrinology 144:51055117, 2003 20. Leary AF, Drury S, Detre S, et al: 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. Clin Cancer Res 16:1486-1497, 2010 21. Chakrabarty A, Rexer BN, Wang SE, et al: H1047R phosphatidylinositol 3-kinase mutant enhances HER2-mediated transformation by heregulin production and activation of HER3. Oncogene 29: 5193-5203, 2010 22. Hurvitz SA, Hu Y, O’Brien N, et al: Current approaches and future directions in the treatment of HER2-positive breast cancer. Cancer Treat Rev 39: 219-229, 2013 23. Laurent-Puig P, Manceau G, Zucman-Rossi J, et al: Dual blockade of epidermal growth factor receptor-induced pathways: A new avenue to treat metastatic colorectal cancer. J Clin Oncol 30:15501552, 2012 24. Vasudevan KM, Barbie DA, Davies MA, et al: AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell 16:21-32, 2009
DOI: 10.1200/JCO.2013.53.5070; published online ahead of print at www.jco.org on March 3, 2014
■ ■ ■
1086
© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at UCSF LIBRARY & CKM on October 4, 2014 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 169.230.243.252
