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Distinct functions of AKT isoforms in breast cancer: a comprehensive review.

ABSTRACT: BACKGROUND:AKT, also known as protein kinase B, is a key element of the PI3K/AKT signaling pathway. Moreover, AKT regulates the hallmarks of cancer, e.g. tumor growth, survival and invasiveness of tumor cells. After AKT was discovered in the early 1990s, further studies revealed that there are three different AKT isoforms, namely AKT1, AKT2 and AKT3. Despite their high similarity of 80%, the distinct AKT isoforms exert non-redundant, partly even opposing effects under physiological and pathological conditions. Breast cancer as the most common cancer entity in women, frequently shows alterations of the PI3K/AKT signaling. MAIN CONTENT:A plethora of studies addressed the impact of AKT isoforms on tumor growth, metastasis and angiogenesis of breast cancer as well as on therapy response and overall survival in patients. Therefore, this review aimed to give a comprehensive overview about the isoform-specific effects of AKT in breast cancer and to summarize known downstream and upstream mechanisms. Taking account of conflicting findings among the studies, the majority of the studies reported a tumor initiating role of AKT1, whereas AKT2 is mainly responsible for tumor progression and metastasis. In detail, AKT1 increases cell proliferation through cell cycle proteins like p21, p27 and cyclin D1 and impairs apoptosis e.g. via p53. On the downside AKT1 decreases migration of breast cancer cells, for instance by regulating TSC2, palladin and EMT-proteins. However, AKT2 promotes migration and invasion most notably through regulation of ?-integrins, EMT-proteins and F-actin. Whilst AKT3 is associated with a negative ER-status, findings about the role of AKT3 in regulation of the key properties of breast cancer are sparse. Accordingly, AKT1 is mutated and AKT2 is amplified in some cases of breast cancer and AKT isoforms are associated with overall survival and therapy response in an isoform-specific manner. CONCLUSIONS:Although there are several discussed hypotheses how isoform specificity is achieved, the mechanisms behind the isoform-specific effects remain mostly unrevealed. As a consequence, further effort is necessary to achieve deeper insights into an isoform-specific AKT signaling in breast cancer and the mechanism behind it.

SUBMITTER: Hinz N

PROVIDER: S-EPMC6873690 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Distinct functions of AKT isoforms in breast cancer: a comprehensive review.

Hinz Nico N Jücker Manfred M

Cell communication and signaling : CCS 20191121 1

<h4>Background</h4>AKT, also known as protein kinase B, is a key element of the PI3K/AKT signaling pathway. Moreover, AKT regulates the hallmarks of cancer, e.g. tumor growth, survival and invasiveness of tumor cells. After AKT was discovered in the early 1990s, further studies revealed that there are three different AKT isoforms, namely AKT1, AKT2 and AKT3. Despite their high similarity of 80%, the distinct AKT isoforms exert non-redundant, partly even opposing effects under physiological and p ...[more]

PMID: 31752925

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Project description:IntroductionAP-2α is a transcription factor implicated in the regulation of differentiation and proliferation in certain tissues, including the mammary gland. In breast tumours, continued expression of AP-2α has been correlated with a better prognosis, but this is hard to reconcile with a reported role in the upregulation of the ERBB2 oncogene. The existence of TFAP2A isoforms, deriving from alternative first exons and differing in their N-terminal sequence, has been described in some mammals, but their relative abundance and activity has not been investigated in the human breast.MethodsExpression levels of four TFAP2A isoforms were assayed at the level of RNA and protein (via the generation of isoform-specific antibodies) in a panel of breast tumour cell lines and in tissue from normal breast and primary tumour samples. Expression constructs for each isoform were used in reporter assays with synthetic and natural promoters (cyclin D3 and ERBB2) to compare the activation and repression activity of the isoforms.ResultsWe demonstrate that the two isoforms AP-2α 1b and AP-2α 1c, in addition to the originally cloned, AP-2α 1a, are conserved throughout evolution in vertebrates. Moreover, we show that isoform 1c in particular is expressed at levels at least on a par with the 1a isoform in breast epithelial lines and tissues and may be more highly expressed in tamoxifen resistant tumours. The isoforms share a similar transactivation mechanism involving the recruitment of the adaptors CITED2 or 4 and the transactivators p300 or CBP. However, isoform 1b and 1c are stronger transactivators of the ERBB2 promoter than isoform 1a. In contrast, AP-2α 1a is the only isoform able to act as a repressor, an activity that requires an intact sumoylation motif present within the N-terminus of the protein, and which the other two isoforms lack.ConclusionsOur findings suggest that TFAP2A isoforms may be differentially regulated during breast tumourigenesis and this, coupled with differences in their transcriptional activity, may impact on tumour responses to tamoxifen therapy. These data also have implications for the interpretation of tumour studies that seek to correlate outcomes with TFAP2A expression level.

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Distinct functions of AKT isoforms in breast cancer: a comprehensive review.

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Distinct functions of AKT isoforms in breast cancer: a comprehensive review.

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