The Kinome Associated with Estrogen Receptor-Positive Status in Human Breast Cancer
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M C Bruce et al. Kinome associated with 21:5 R357–R370 Review ER-positive status The kinome associated with estrogen receptor-positive status in human breast cancer Correspondence M Christine Bruce, Danielle McAllister and Leigh C Murphy should be addressed to L C Murphy Department of Biochemistry and Medical Genetics, Manitoba Institute of Cell Biology, University of Manitoba Email and CancerCare Manitoba, 675 McDermot Avenue, Winnipeg, Manitoba, Canada R3E 0V9 Leigh.Murphy@ med.umanitoba.ca Abstract Estrogen receptor alpha (ERa) regulates and is regulated by kinases involved in several Key Words functions associated with the hallmarks of cancer. The following literature review strongly " estrogen receptors suggests that distinct kinomes exist for ERa-positive and -negative human breast cancers. " breast cancer Importantly, consistent with the known heterogeneity of ERa-positive cancers, different " phosphorylation subgroups exist, which can be defined by different kinome signatures, which in turn are " kinases correlated with clinical outcome. Strong evidence supports the interplay of kinase networks, " endocrine therapy sensitivity suggesting that targeting a single node may not be sufficient to inhibit the network. " biomarker Therefore, identifying the important hubs/nodes associated with each clinically relevant kinome in ERC tumors could offer the ability to implement the best therapy options at diagnosis, either endocrine therapy alone or together with other targeted therapies, Endocrine-Related Cancer for improved overall outcome. Endocrine-Related Cancer (2014) 21, R357–R370 Introduction The idea of personalized approaches to therapy in breast therapy was used for breast cancer at least in the form of cancer based on the molecular nature of the tumor can be ablation surgery such as ovariectomy dates back well over traced back to the late 1960s and early 1970s, when it was a century, the identification of ERs in breast cancers discovered that some but not all human breast tumors provided a molecular mechanism and rationale for the use express estrogen receptors (ERs; Jensen et al. 1971). This of hormonal therapies (Jensen & Jordan 2003). This led heralded the beginning of an era of targeted therapies for directly to the development of the successful modern breast cancer, identified the first biomarker used clinically endocrine therapies such as tamoxifen and other selective to predict the biological behavior of breast cancer, and estrogen receptor modulators (SERMs), which bind to the established the beginnings of understanding molecular ERs and induce conformational changes that modify and mechanisms by which the ovarian hormone, estrogen, in some cases inactivate the ERs (Jensen & Jordan 2003). drives the growth and survival of the majority of human The newer endocrine therapies, the aromatase inhibitors breast cancers (Jensen & Jordan 2003), at least initially. (AIs), which inhibit the aromatase enzyme, eliminate the Inhibiting the activity of ERs with the antiestrogen production of estrogen and therefore inhibit estrogen’s tamoxifen was the first targeted therapy in breast cancer. proliferative action (Goss et al. 2011). Although the knowledge that female hormones were It was evident from the start that not all ERC breast involved in breast cancer and the hormonal/endocrine tumors were created equal. Although a little more than http://erc.endocrinology-journals.org q 2014 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/ERC-14-0232 Printed in Great Britain Downloaded from Bioscientifica.com at 10/04/2021 07:16:28PM via free access Review M C Bruce et al. Kinome associated with 21:5 R358 ER-positive status 70% of all breast tumors express ER, only about half of (Yamnik et al. 2009, Yamnik & Holz 2010, Murphy et al. patients with ERC tumors respond to tamoxifen. There- 2011), as well as the demonstration that a clinically fore, ERC breast cancers exhibit heterogeneity associated relevant phosphorylation profile of ERs can be identified with prognosis and treatment outcomes. The first step to in human breast cancer (Skliris et al. 2010a), suggests that resolve this heterogeneity came from the idea that the kinases and/or phosphatases associated with ERC breast measurement of a downstream target of estrogen- cancer could provide a wealth of potential drug targets to dependent ER signaling such as the progesterone receptor complement existing endocrine therapies or generate new (PR) would increase confidence that the pathway was endocrine therapies. The following is a review of kinases intact (Horwitz et al. 1975). This increased the accuracy of that have been identified as associated with ER status in treatment prediction, but was obviously still imprecise as breast tumors or those that have been implicated in the some 20–30% of ERC/PRC tumors are de novo resistant to regulation of estrogen signaling and/or modifying sensi- the endocrine therapies. Furthermore, initial response to tivity to estrogen and its antagonists in breast cancer. endocrine therapies is often followed by acquired resist- ance despite the continued expression of ER (Encarnacion Kinases identified as mutated or structurally et al. 1993, Bachleitner-Hofmann et al. 2002). altered in breast cancer in large breast cancer The next significant insight into the heterogeneity of cohorts ERC breast cancer came with the identification of HER2 (ERBB2) amplification. Approximately 20% of all breast Genome-wide analyses of large cohorts of breast cancer cancers have amplified, overexpressed HER2, and 40–50% cases are providing detailed, comprehensive analyses of of these will also be ERC. Interestingly, ERC/HER2C genomic aberrations in breast cancer at a population level. tumors are more likely to be resistant to endocrine Some studies have also provided data concerning their therapy, in particular tamoxifen, thus providing impact on clinical characteristics. These studies have important insight into the relevance of crosstalk of shown that many of the frequently altered (amplified, signaling pathways initiated at the level of the plasma fused, deleted, or mutated) genes encode kinases. Some of membrane with many aspects of the ER signaling these frequently altered genes, such as HER2,were pathway. This may cause ligand-independent activation previously known but others, such as MAP3K1 and its of ER signaling and hormone therapy resistance. substrate MAP2K4, have not previously been identified to The molecular detailing that has become possible have functional roles in breast cancer. However, given that Endocrine-Related Cancer through the Human Genome Project and new high- enzymes, kinases in particular, have proven to be clinically throughput/high-content technologies in the last decade efficacious therapeutic targets, a wealth of data has now initially established five intrinsic molecular subgroups been generated not only to understand the complex (Sorlie et al. 2003) of which three were significantly biology of the disease but also to identify new treatments populated with ERC tumors. Most recently, at least ten for specific cohorts. molecular subgroups of human breast cancer have been The recently published METABRIC cohort of breast described (Curtis et al.2012) and eight of these appeared to cancers, in which 2000 individual breast cancers were be significantly populated with ERC tumors (Curtis et al. interrogated, identified ten integrative clusters, each with 2012). Associated with these studies has been the frequent distinct molecular characteristics associated with clinical identification of kinases, either mutated and/or structurally outcome (Curtis et al.2012). Often, altered genes encoding altered in large cohorts of breast tumors (Banerji et al.2012, kinases and phosphatases dominate individual clusters Curtis et al.2012, Shah et al.2012, Stephens et al.2012). (Table 1). Furthermore, the original intrinsic subtypes, in Some of these have also been found frequently altered and particular the ERC luminal A and luminal B (Perou et al. associated with AI sensitivity (Ellis et al.2012). 2000, Ignatiadis & Sotiriou 2013) subtypes, have been ER and its many coactivators are regulated by further subdivided due to the METABRIC study (Curtis et al. phosphorylation as well as other post-translational 2012, Dawson et al.2013). Therefore, a brief description of modifications (PTMs; Rowan et al. 2000, York et al. 2010, this follows as it relates to clusters that have significant Le Romancer et al. 2011, Zhang et al. 2013). The discovery ERC components. that the ER and its coactivators are substrates of several METABRIC integrative cluster 1 (IntClust1), represent- kinases (enzymes causing phosphorylation of specific ing 7% of breast cancer (Curtis et al.2012, Dawson et al. substrates), which are regulated by signaling pathways 2013), contains predominantly ERC tumors with luminal B frequently mutated or structurally altered in breast cancer features and is characterized by amplification of the http://erc.endocrinology-journals.org q 2014 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/ERC-14-0232 Printed in Great Britain Downloaded from Bioscientifica.com at 10/04/2021 07:16:28PM via free access Review M C Bruce et al. Kinome associated with 21:5 R359 ER-positive status Table 1 Kinases and phosphatases altered in ERC-dominated its amplification in this region. A high frequency (w50%) breast cancer clusters from METABRIC (Curtis et al.2012, of PI3K catalytic subunit p110a (PIK3CA) mutations is also Dawson et al. 2013) observed in this group.