Akt
AKTの脂質結合部位のアミノ酸置換（グルタミン酸17からリシン）で乳がん、大腸がん、卵巣がんが報告されている。リン酸イノシチドと新たな水素結合を形成することでAKT1が活性化される。
Carpten et al. (2007) reported the identification of a somatic mutation in human breast, colorectal, and ovarian cancers that results in a glutamic acid-to-lysine substitution at amino acid 17 (see 164730.0001) in the lipid-binding pocket of AKT1. Lys17 alters the electrostatic interactions of the pocket and forms new hydrogen bonds with a phosphoinositide ligand. This mutation activates AKT1 by means of pathologic localization to the plasma membrane, stimulates downstream signaling, transforms cells, and induces leukemia in mice. Carpten et al. (2007) concluded that this mechanism indicates a direct role of AKT1 in human cancer, and adds to the known genetic alterations that promote oncogenesis through the phosphatidylinositol-3-OH kinase/AKT pathway. Furthermore, Carpten et al. (2007) suggested that the E17K substitution decreases the sensitivity to an allosteric kinase inhibitor, so this mutation may have important clinical utility for AKT drug development.
ESR1
エストロゲン受容体の存在は乳がん患者で再発の危険性を低め、より高い生存率を示すことは受け入れられてきた。
受容体の状態はホルモン治療の反応性のガイドラインとなる。変異により短縮した受容体でホルモン無しで転写が活性化されるようなケースでホルモンに反応しなくなる。
It is accepted that the presence of estrogen receptor identifies those breast cancer patients with a lower risk of relapse and better overall survival (Clark and McGuire, 1988), and the measurement of ESR has become a standard assay in the clinical management of breast cancer. Receptor status also provides a guideline for those tumors that may be responsive to hormonal intervention. But only about half of ESR-positive patients respond to various hormonal therapies and of those who do respond initially, most will eventually develop hormonally unresponsive disease following a period of treatment even though ESR is often still present. Sluyser and Mester (1985) hypothesized that the loss of hormone dependence of certain breast tumors may be due to the presence of mutated or truncated steroid receptors that activate transcription even in the absence of hormone.
Fuqua et al. (1993) reviewed ESR mutations that may be important in breast cancer progression.
Scott et al. (1991), for example, had found truncated forms of DNA-binding ESR in human breast cancer.
To better understand structure-activity relationships of the human estrogen receptor, Weis et al. (1996) examined the role of tyrosine-537 in transcriptional response of the receptor. This residue is close to a region of the hormone-binding domain shown previously to be important in hormone-dependent transcriptional activity; it also has been proposed to be a tyrosine kinase phosphorylation site important in ESR activity. Weis et al. (1996) substituted 5 amino acids at this position (alanine, phenylalanine, glutamic acid, lysine, or serine) and screened these mutants for their biologic activities in the presence and absence of estradiol. Two of the ESR mutants, tyr537 to ala and tyr537 to ser, displayed estrogen-independent constitutive activity that was approximately 20% or 100%, respectively, of the activity of the wildtype receptor with estradiol. In some circumstances, the tyr537-to-glu and tyr537-to-lys proteins also exhibited some low level of constitutive activity. Their findings indicated that tyrosine-537 is in a region important in the ligand regulation of ESR transcriptional activity and that certain amino acid substitutions at this position can shift ESR into a conformation that is active even without ligand.
Sluyser (1995) reviewed the somatically generated mutations in ESR that had been found at the mRNA/cDNA level in human breast cancer biopsies and in established breast cancer cell lines. Aberrantly spliced ESR mRNA causes the appearance of truncated or internally deleted ESR protein forms. Studies on the functional activity of ESR variants in expression systems demonstrated dominant-positive receptors that are transcriptionally active in the absence of estrogen, and dominant-negative receptors that are themselves transcriptionally inactive but that prevent the action of the normal receptor. The ESR variants are believed to confer resistance to endocrine therapy in breast cancer patients. Abnormally spliced forms of ESR, similar to those in breast cancer, were reported by McGuire et al. (1992) and by others. In all, 19 somatic mutations were tabulated and mapped on a diagram of the structural organization of the ESR gene.
Andersen et al. (1997) studied leukocyte DNA from 143 patients with familial clustering of breast and/or ovarian cancer and tumor DNA from 96 breast carcinomas for base mutations in the ESR gene. Three patients with a family history of cancer were carrying a gly160-to-cys germline substitution, which they concluded represents a polymorphism because it was detected in 4 females and 4 males of 729 controls, split about equally between males and females. However, in the 229 female controls in whom family history of cancer was known, 1 of 2 who had a sister with breast cancer was carrying the variant allele; hence, a possible clinical significance of the gly160-to-cys change should be further investigated. Somatic mutations were not detected in any of the tumors studied, and the data did not provide support for somatic ESR base mutations as an important mechanism for hormonal therapy resistance in estrogen receptor-positive breast carcinomas.
Using an Affymetrix 10K SNP array to screen for gene copy number changes in breast cancer, Holst et al. (2007) detected a single-gene amplification of the ESR1 gene. A subsequent tissue microarray analysis of more than 2,000 clinical breast cancer samples showed ESR1 amplification in 20.6% of breast cancers. In 99% of tumors with ESR1 amplification, overexpression of estrogen receptor protein was demonstrated, compared with 66.6% of cancers without ESR1 amplification. In 175 women who had received adjuvant tamoxifen monotherapy, survival was significantly longer for women with cancer with ESR1 amplification than for women with estrogen receptor-expressing cancers without ESR1 amplification (P = 0.023). Notably, they also found ESR1 amplification in benign and precancerous breast diseases, suggesting that ESR1 amplification may be a common mechanism in proliferative breast disease and a very early genetic alteration in a large subset of breast cancers.
In correspondences, Brown et al. (2008), Horlings et al. (2008), Vincent-Salomon et al. (2008), and Reis-Filho et al. (2008) reported attempts to replicate the finding of Holst et al. (2007) of a high frequency of ESR1 amplification in breast cancer. No group was able to replicate the results of Holst et al. (2007), using a variety of methods including array comparative genomic hybridization (CGH), FISH, and quantitative PCR. Amplification was found at a frequency of approximately 10% or less (Albertson, 2008). In a discussion of the findings of all of these groups, Albertson (2008) noted that although Holst et al. (2007) reported to have followed the standard procedure for scoring FISH, i.e., to count closely spaced signals as 1 signal, in their reply to the contesting groups Holst et al. (2008) emphasized the importance of scoring clusters of signals. Holst et al. (2008) stated, 'In our laboratory, most ESR1-amplified tumors have small gene clusters that could be considered as one signal if 'ERBB criteria' were applied....We therefore feel that estimating the ESR1 gene copy number may--given the currently available reagents--enable a more reliable identification of amplified cancers than classical counting.' Albertson (2008) concluded that this and other discrepancies, including that involving the clinical significance concerning prognosis, indicated that 'the jury is still out on the question of ESR1 amplification and its clinical significance.'
Certain malignant breast tumors (see 114480) are characterized by a high prediction uncertainty ('low-confidence') with respect to ESR status. Kun et al. (2003) analyzed these 'low-confidence' tumors and determined that their uncertain prediction status arose as a result of widespread perturbations in multiple genes whose expression is important for ESR-subtype discrimination. Patients with 'low-confidence' ESR-positive tumors exhibited a significantly worse overall survival (p = 0.03) and shorter time to distant metastasis (p = 0.004) compared with their 'high-confidence' ESR-positive counterparts. Elevated expression of ERBB2 (164870) was significantly correlated with a breast tumor exhibiting a 'low-confidence' prediction. Although ERBB2 signaling has been proposed to inhibit the transcriptional activity of ESR1, a large proportion of the perturbed genes in the 'low-confidence'/ERBB2-positive samples are not known to be estrogen responsive. Kun et al. (2003) proposed that a significant portion of the effect of ERBB2 on ESR-positive breast tumors may involve ESR-independent mechanisms of gene activation, which may contribute to the clinically aggressive behavior of the 'low-confidence' breast tumor subtype.
Toy et al. (2013) conducted a comprehensive genetic analysis of 2 independent cohorts of metastatic ER-positive breast tumors and identified mutations in ESR1 affecting the ligand-binding domain (LBD) in 14 of 80 cases. These included highly recurrent mutations encoding tyr537 to ser, tyr537 ro asn, and asp538 to gly alterations. Molecular dynamics simulations suggested that the structures of the tyr537 to ser and asp538 to gly mutants involve hydrogen bonding of the mutant amino acids with asp351, thus favoring the agonist conformation of the receptor. Consistent with this model, mutant receptors drive ER-dependent transcription and proliferation in the absence of hormone and reduce the efficacy of ER antagonists.
Robinson et al. (2013) enrolled 11 patients with ER-positive metastatic breast cancer in a prospective clinical sequencing program for advanced cancers. Whole-exome and transcriptome analysis identified 6 cases that harbored mutations of ESR1 affecting its LBD, all of whom had been treated with antiestrogens and estrogen deprivation therapies. A survey of The Cancer Genome Atlas identified 4 endometrial cancers with similar mutations of ESR1. The 5 LBD-localized ESR1 mutations identified, encoding leu536 to gln, tyr537 to ser, tyr537 to cys, tyr537 to asn, and asp538 to gly, were shown to result in constitutive activity and continued responsiveness to antiestrogen therapies in vitro.
