The infraacetabular screw versus the antegrade posterior column screw in acetabulum fractures with posterior column involvement: a biomechanical comparison.

INTRODUCTION: Traditionally, plate osteosynthesis of the anterior column combined with an antegrade posterior column screw is used for fixation of anterior column plus posterior hemitransverse (ACPHT) acetabulum fractures. Replacing the posterior column screw with an infraacetabular screw could improve the straightforwardness of acetabulum surgery, as it can be inserted using less invasive approaches, such as the AIP/Stoppa approach, which is a well-established standard approach. However, the biomechanical stability of a plate osteosynthesis combined with an infraacetabular screw instead of an antegrade posterior column screw is unknown. MATERIAL AND METHODS: Two osteosynthesis constructs were compared in a synthetic hemipelvis model with an ACPHT fracture: Suprapectineal plate + antegrade posterior column screw (APCS group) vs. suprapectineal plate + infraacetabular screw (IAS group). A single-leg stance test protocol with an additional passive muscle force and a cyclic loading of 32,000 cycles with a maximum effective load of 2400 N was applied. Interfragmentary motion and rotation of the three main fracture lines were measured. RESULTS: At the posterior hemitransverse fracture line, interfragmentary motion perpendicular to the fracture line (p < 0.001) and shear motion (p < 0.001) and at the high anterior column fracture line, interfragmentary motion longitudinal to the fracture line (p = 0.017) were significantly higher in the IAS group than in the APCS group. On the other hand, interfragmentary motion perpendicular (p = 0.004), longitudinal (p < 0.001) and horizontal to the fracture line (p = 0.004) and shear motion (p < 0.001) were significantly increased at the low anterior column fracture line in the APCS group compared to the IAS group. CONCLUSIONS: Replacing the antegrade posterior column screw with an infraacetabular screw is not recommendable as it results in an increased interfragmentary motion, especially at the posterior hemitransverse component of an ACPHT fracture.

Short stem hip arthroplasty with the optimys prosthesis is a safe and effective option for obese patients: a mid-term follow-up multicenter study.

INTRODUCTION: Short stems are a valuable option in young patients undergoing total hip arthroplasty (THA) because of their bone stock preserving properties facilitating revision hip arthroplasty. Although the effect of obesity on conventional THA is well studied, data about short stem THA in obese patients are lacking. Therefore, this study aimed to investigate the influence of obesity on complications, revisions, and outcome after short stem THA. MATERIALS AND METHODS: This multicenter, observational cohort study included patients undergoing short stem THA with the optimys prosthesis. Follow-up examinations were performed at specific intervals up to 7 years postoperatively. Operation characteristics, general and specific complications, revisions, VAS rest pain, VAS load pain, VAS patient satisfaction, and Harris Hip Score (HHS) were recorded and statistically compared between obese (BMI ≥ 30 kg/m2) and non-obese (BMI < 30 kg/m2) patients. RESULTS: Of the 224 patients included with a mean follow-up of 87.2 months (range 81.9-104.0), 69 were assigned to the OB group and 155 to the non-OB group. A minimally invasive approach was significantly less often selected in obese patients (p = 0.049), whereas operating time and length of hospital stay were not significantly different. The rate of general and specific complications did not significantly differ between both groups. Survival of the optimys prosthesis was 99.1% at 7-year follow-up and one patient per group had to undergo revision surgery. VAS rest pain, load pain, and satisfaction improved from preoperatively to postoperatively in both groups without a significant difference between both groups. While the HHS was improved from preoperatively to postoperatively, obese patients showed a significantly lower HHS at the 7-year follow-up (p = 0.01) but still exhibited an excellent scoring above the PASS threshold. CONCLUSION: Short stem THA with the optimys prosthesis is a safe and effective option also in obese patients with an excellent clinical outcome and a low complication rate.

Increased local bone turnover in patients with chronic periprosthetic joint infection.

Aims: The management of periprosthetic joint infection (PJI) remains a major challenge in orthopaedic surgery. In this study, we aimed to characterize the local bone microstructure and metabolism in a clinical cohort of patients with chronic PJI. Methods: Periprosthetic femoral trabecular bone specimens were obtained from patients suffering from chronic PJI of the hip and knee (n = 20). Microbiological analysis was performed on preoperative joint aspirates and tissue specimens obtained during revision surgery. Microstructural and cellular bone parameters were analyzed in bone specimens by histomorphometry on undecalcified sections complemented by tartrate-resistant acid phosphatase immunohistochemistry. Data were compared with control specimens obtained during primary arthroplasty (n = 20) and aseptic revision (n = 20). Results: PJI specimens exhibited a higher bone volume, thickened trabeculae, and increased osteoid parameters compared to both control groups, suggesting an accelerated bone turnover with sclerotic microstructure. On the cellular level, osteoblast and osteoclast parameters were markedly increased in the PJI cohort. Furthermore, a positive association between serum (CRP) but not synovial (white blood cell (WBC) count) inflammatory markers and osteoclast indices could be detected. Comparison between different pathogens revealed increased osteoclastic bone resorption parameters without a concomitant increase in osteoblasts in bone specimens from patients with Staphylococcus aureus infection, compared to those with detection of Staphylococcus epidermidis and Cutibacterium spp. Conclusion: This study provides insights into the local bone metabolism in chronic PJI, demonstrating osteosclerosis with high bone turnover. The fact that Staphylococcus aureus was associated with distinctly increased osteoclast indices strongly suggests early surgical treatment to prevent periprosthetic bone alterations.

Comparison of different intraoperative reduction monitoring methods in a cadaveric intraarticular calcaneal fracture model: 3D scan vs arthroscopy vs nanoscopy.

AIMS: Visualization of the subtalar joint surface in surgical management of calcaneal factures remains a big challenge and anatomic reduction of the articular surface is essential for a good clinical outcome. We hypothesize that video-assistance can provide superior fracture reduction compared to fluoroscopy and that nanoscopy (NSC) achieves more extensive visualization compared to fracturoscopy (FSC). METHODS: Ten human cadaveric feet with artificially pre-fractured intraarticular calcaneal fractures with involvement of the posterior facet were treated via a minimal invasive subtalar approach. After initial control of reduction by 2D fluoroscopy, the reduction was further analyzed intraoperatively by FSC and NSC. 3D Scan served as gold standard control of reduction. Need of revision of reduction after the different visualization techniques was recorded and the extent of visualization of the subtalar joint surface in the medio-lateral dimension was compared for FSC and NSC. To quantify access and visualization of the medial and posterior facet, a depth gauge was used to measure from laterally at the clinically widest portion of the calcaneus targeted to the sustentaculum tali. The distance in millimetres was referred to the complete medio-lateral distance seen on paracoronal CT at the widest portion of the calcaneus. RESULTS: Fracture analysis in preoperative CT-scans according to Sanders classification revealed four type IC, two IIA, three IIC and one IIIAC fractures. Mean visualization of the medial and posterior facet was significantly improved with NSC (30.4 ± 3.78 mm) compared to FSC (23.6 ± 6.17 mm) (p = 0.008). An imperfect reduction requiring revision was more often required with NSC compared to FSC. Insufficient reduction using video-assistance was found in two cases. CONCLUSION: In order to optimize subtalar joint reduction and congruency, video-assisted techniques, especially NSC, provide superior visualization and thus can improve reduction in the surgical treatment of intraarticular calcaneal fractures.

Lateral cortical notching facilitates dynamization of proximal femoral nailing - A finite element analysis.

INTRODUCTION: Dynamization of proximal femoral nailing by removal of distal interlocking is one of the recommended treatment options for nonunions of femur fractures. However, in certain inter-/subtrochanteric fractures, gliding of the nail along the femoral shaft is blocked by lateral femoral cortical support of the lag screw. For these cases, Biber et al. proposed lateral cortical notching (LCN), in which the supporting lateral bone is removed. This study investigates the biomechanical effect of LCN on gliding of proximal femoral nailing and stress distribution at the bone/implant interface. MATERIALS AND METHODS: In this finite element analysis a three-dimensional model of an unstable intertrochanteric fracture with proximal femoral nailing without distal interlocking was simulated using the FebioStudio software suite. To simulate LCN, the lag screw hole was lengthened to 15.34 mm at the lateral cortex. Displacement of the nail along the femoral shaft axis and von Mises stress distribution were compared between LCN model and standard implantation model. RESULTS: Displacement of the nail along the femoral shaft axis was higher in the LCN model than in the standard implantation model (0.48 mm vs. 0.07 mm). Highest von Mises stresses of 176-178 MPa at the implant and of 52-81 MPa at the proximal femur were detected. Maximum von Mises stresses of the implant were comparable at all sides, except for a reduced von Mises stress at the lateral inferior side in the LCN model (80 vs. 102 MPa). At the inferior lateral screw hole and the anterior/posterior lateral screw hole maximum von Mises stress was reduced in the LCN model (2 vs. 49 MPa and 52 vs. 81 MPa), whereas the maximum von Mises stress at the inferior medial screw hole was higher in the LCN model than in the standard implantation model (53 vs. 27 MPa). CONCLUSIONS: Lateral cortical notching facilitates gliding of a distally dynamized proximal femoral nail along the femoral shaft axis in intertrochanteric fractures. Additionally, the lack of lateral cortical bone support at the lag screw reduces von Mises stress at the bone/implant interface and thus could lower the risk for implant breakage and peri­implant fractures.

Epidemiology and socioeconomic consequences of work-related pelvic and acetabular fractures recorded in the German Social Accident Insurance.

INTRODUCTION: Pelvic and acetabular fractures can result from work-related accidents and frequently require lengthy medical treatments. Consequently, high medical costs as well as delayed or absent return to work can be the consequence. Therefore, we aimed to study the socioeconomic consequences of work-related pelvic and acetabular fractures. MATERIALS AND METHODS: This retrospective study investigated work-related pelvic and acetabular fractures recorded in the German Social Accident Insurance in 2011 and 2017, in terms of age, sex, type of accident, duration of incapacity to work, reductions in earning capacity, costs for outpatient and inpatient treatment and costs for pension and severance pay. RESULTS: Among a total of 606 injuries in 2011 and 619 injuries in 2017, male patients and patients between 40 and 65 years were predominantly affected. Acetabular fractures caused higher rates of long absence from work of 6-12 months (2011: 24.7% vs. 9.5-16.9%; 2017: 26.1% vs. 6.1-11.0%) and >12 months (2011: 15.8% vs. 9.8-10.2%; 2017: 13.3% vs. 1.9-8.2%) as well as more cases with a reduction in earning capacity of at least 20% (2011: 61 vs. ≤27 cases; 2017: 39 vs. ≤12 cases) compared to pelvic ring fractures. The total costs for pelvic ring and acetabular fractures in the German social accident insurances amounted € 18,726,630 and € 9637,189 in the periods 2011-2020 and 2017-2020, respectively. The average costs per case for treatment and rehabilitation until 2020 was € 19,079 for injuries from 2011 and € 13,629 for injuries from 2017. Acetabular fractures were found to be the most cost-intensive injuries compared to anterior, posterior or complex pelvic ring fractures. CONCLUSIONS: Work-related pelvic and especially acetabular fractures have a considerable socioeconomic impact in the German Social Accident Insurance. Measures to prevent work-related accidents and to improve treatment of pelvic injuries can help to reduce their socioeconomic burden.

A Register Analysis after Tibial Plateau Fracture in Statutory Accident Insurance. / Ergebnisse und Kosten nach Tibiakopffraktur in der gesetzlichen Unfallversicherung ­ eine Registeranalyse.

OBJECTIVE: To analyse the results after tibial plateau fractures with a focus on socioeconomic consequences. METHODS: On the basis of the data from the rehabilitation documentation of the German Statutory Accident Insurance (DGUV) on tibial plateau fractures (Code 83), a retrospective anonymised evaluation of the injuries which occurred in 2010 and 2016 was carried out. The registry data allowed subdivision into 3 groups: Medial, lateral and bicondylar tibial plateau fractures. The data have been analysed with regard to the following parameters: age, gender, treatment, time of return to work (AU), costs per case, total costs, workers compensation (MdE) and total payments. RESULTS: The analysis includes 1046 isolated tibial plateau fractures for 2010 and 1072 for 2016. In 2016, 798 fractures could be assigned to the medial, lateral or bicondylar fracture groups. In 551 cases, both condyles were involved. In another 221 cases, the lateral plateau and in 26 the medial plateau was injured. There were 476 (59.7%) men and 322 (40.4%) women. The mean age was 43.4 (SD ± 16.7) years with a peak of 180 cases in the 55-60 year subgroup and 98 aged 15-20 years. The mean age of the cases with isolated lateral plateau involvement was 48.1 (SD ± 13.8) and was 47.5 (SD ± 16.6) in those with medial plateau fractures and 41.4 (SD ± 17.2) years in the subgroup with bicondylar patterns. The mean time of return to work was 39.4 (SD ± 25.3) weeks for the bicondylar tibial plateau fractures, 28.1 (SD ± 27.2) weeks for the medial and 24.5 (SD ± 22.8) weeks for the lateral groups. For the 2016 group, the mean costs were 5212 € for outpatient, 10358 € for inpatient and 7622 € for rehab costs per case (total costs over three years of 4247443 € for outpatient and 7506508 € for acute inpatient treatment). The highest costs per case were caused by the inpatient acute treatment of bicondylar tibial plateau fractures, at a mean of 22292 €. 17.6% of the 2016 casualty group resulted in compensation of at least 20%. The treatment costs for the 2010 group over 9 years (2010-2019) amounted to 4190855 € for outpatient treatments and € 9565313 for inpatient treatments. In addition, compensations of 8632448 € and lump-sum payments of 483289 € were paid from 2010 to 2019. Over a period of 9 years, 456 (66%) of 692 patients needed another in patient follow-up treatment. A total of 51% (n = 353) needed these treatments within the first year. CONCLUSION: Tibial plateau fractures, in particular bicondylar tibial plateau fractures, show long-term, cost-intensive healing processes with reduced occupational capacity. Tibial plateau fractures are of economic importance in the statutory accident insurance in the long term. Preventive measures, optimal care and rehabilitation are therefore essential, together with innovative research to improve clinical outcomes.

Neurogenic gluteus medius and minimus muscle atrophy with Trendelenburg's sign after a displaced acetabular fracture of the posterior column - A case report.

Traumatic or iatrogenic sciatic nerve injury, but not superior gluteal nerve injury, is a well described complication after acetabular fractures. Most often, sciatic nerve injuries occur in fractures involving the posterior column/wall with a hip dislocation and posterior fracture displacement resulting in narrowing of the greater sciatic foramen and injuring the sciatic nerve passing through. In this case report, a case of abductor mechanism deficiency with positive Trendelenburg's sign after an acetabular fracture of the posterior column with hip dislocation is presented. Postoperative clinical and MRI examination revealed a neurogenic atrophy of gluteus medius and minimus muscles suggesting a superior gluteal nerve injury due to initial subtotal incarceration of the greater sciatic foramen by a displaced posterior fracture fragment. An additional mild sciatic nerve injury resolved in the early postoperative course, while intensive physiotherapy improved the patient's complaints and muscular atrophy caused by the superior gluteal nerve injury within 12 months. This case report intends to raise awareness for rare neurological complications after acetabular fractures for their early detection.

Impaired Bone Microarchitecture at Distal Radial and Tibial Reference Locations Is Not Related to Injury Site in Athletes With Bone Stress Injury.

BACKGROUND: Bone stress injuries (BSIs) are common sports injuries that occur because of an imbalance between microdamage accumulation and removal through bone remodeling. The underlying bone phenotype has been assumed to be a contributing factor. However, the bone microarchitecture of athletes with BSI is not well characterized, and no study has investigated whether impaired bone microarchitecture is associated with bone composition or anatomic site of injury. PURPOSE/HYPOTHESIS: This cross-sectional study characterizes the bone microarchitecture at distal radial and tibial reference locations in athletes with BSI. Based on previous dual-energy X-ray absorptiometry (DXA) findings, the aim was to compare anatomic injury sites, hypothesizing that athletes with BSIs in bones with greater trabecular composition show impaired bone microarchitecture parameters compared with those with BSIs in bones with greater cortical composition. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Athletes who had presented to our outpatient clinic because of a high-grade BSI (ie, stress fracture) were retrospectively included. Blood and urine samples were collected. Areal bone mineral density (aBMD) was assessed by DXA at the lumbar spine and both hips. Bone microarchitecture was analyzed by high-resolution peripheral quantitative computed tomography (HR-pQCT) at the distal radius and tibia. HR-pQCT parameters were expressed in relation to available sex-, age-, and device-adjusted reference values and compared with a cohort of 53 age- and sex-matched controls. RESULTS: In total, 53 athletes had a BSI of the foot (n = 20), tibia/fibula (n = 18), pelvis (n = 9), femur (n = 5), or sternum (n = 1). Based on DXA measurements, a Z-score of -1.0 or lower was found in 32 of 53 (60.4%) of the athletes, of whom 16 of 53 (30.2%) had a Z score -2.0 or lower. While an impairment of cortical area (P = .034 and P = .001) and thickness (P = .029 and P < .001) was detected at the distal radius and tibia in the BSI cohort compared with controls, no differences in BMD or bone microarchitecture were observed between anatomic injury sites. Furthermore, no difference was revealed when BSIs were grouped into cortical- and trabecular-rich sites. CONCLUSION: Reduced aBMD and impaired cortical bone microarchitecture were present in a considerable number of athletes with BSI. Neither aBMD nor bone microarchitecture was related to the injury site, highlighting the multifactorial etiology of BSI.

Biomechanical in vitro analysis of a novel flexible implant for pubic symphysis disruption using an ultra-high molecular weight polyethylene fiber cord.

BACKGROUND: Plate osteosynthesis depicts the gold standard to surgically treat pubic symphysis disruptions. However, high rates of implant failure after plate osteosynthesis are reported, probably because of the iatrogenic arthrodesis of this fibrocartilaginous joint. Therefore, flexible implants for treatment of pubic symphysis disruptions appear to be a sensible solution. METHODS: In this biomechanical screening study, we designed and investigated a flexible implant, which consists of two plates connected with an ultra-high molecular weight polyethylene fiber cord. We mechanically tested eye splices as a possible fixation method of the cords by performing tensile load to failure tests. Afterwards, we developed a biomechanically appropriate plate design and cord routing between the plates. Finally, we biomechanically tested the flexible implant under tensile and shear loading until failure. FINDINGS: When fixing a 1 mm ultra-high molecular weight polyethylene fiber cord with eye splices, a load at failure of 1570.74 N was detected under tensile loading. None of the eye splices failed but the cords itself ruptured. The load at failure of the designed cord routing in criss-cross technique and fixation within the plates amounts 4742.09 N under tensile and 2699.77 N under shear load. INTERPRETATION: We developed a novel flexible implant for repair of pubic symphysis disruptions using ultra-high molecular weight polyethylene fiber cords connected to osteosynthesis plates. We identified eye splices as a mechanically optimal fixation method and proved that the ultra-high molecular weight polyethylene fiber cord routing and fixation of the flexible implant clearly withstands physiological forces acting on the pubic symphysis.

Biomechanical analysis of fixation methods in acetabular fractures: a systematic review of test setups.

PURPOSE: Optimal anatomical reduction and stable fixation of acetabular fractures are important in avoiding secondary dislocation and osteoarthritis. Biomechanical studies of treatment options of acetabular fractures aim to evaluate the biomechanical properties of different fixation methods. As the setup of the biomechanical test can influence the experimental results, this review aimed to analyze the characteristics, comparability and clinical implications of studies on biomechanical test setups and finite element analyses in the fixation of acetabular fractures. METHODS: A systematic literature research was conducted according to the PRISMA guidelines, using the PubMed/MEDLINE and Web of Science databases. 44 studies conducting biomechanical analyses of fixation of acetabular fractures were identified, which met the predefined inclusion and exclusion criteria and which were published in English between 2000 and April 16, 2021. The studies were analyzed with respect to distinct parameters, including fracture type, material of pelvis model, investigated fixation construct, loading direction, loading protocol, maximum loading force, outcome parameter and measurement method. RESULTS: In summary, there was no standardized test setup within the studies on fixation constructs for acetabular fractures. It is therefore difficult to compare the studies directly, as they employ a variety of different test parameters. Furthermore, the clinical implications of the biomechanical studies should be scrutinized, since several test parameters were not based on observations of the human physiology. CONCLUSION: The limited comparability and restricted clinical implications should be kept in mind when interpreting the results of biomechanical studies and when designing test setups to evaluate fixation methods for acetabular fractures.

AKT in Bone Metastasis of Solid Tumors: A Comprehensive Review.

Solid tumors, such as breast cancer and prostate cancer, often form bone metastases in the course of the disease. Patients with bone metastases frequently develop complications, such as pathological fractures or hypercalcemia and exhibit a reduced life expectancy. Thus, it is of vital importance to improve the treatment of bone metastases. A possible approach is to target signaling pathways, such as the PI3K/AKT pathway, which is frequently dysregulated in solid tumors. Therefore, we sought to review the role of the serine/threonine kinase AKT in bone metastasis. In general, activation of AKT signaling was shown to be associated with the formation of bone metastases from solid tumors. More precisely, AKT gets activated in tumor cells by a plethora of bone-derived growth factors and cytokines. Subsequently, AKT promotes the bone-metastatic capacities of tumor cells through distinct signaling pathways and secretion of bone cell-stimulating factors. Within the crosstalk between tumor and bone cells, also known as the vicious cycle, the stimulation of osteoblasts and osteoclasts also causes activation of AKT in these cells. As a consequence, bone metastasis is reduced after experimental inhibition of AKT. In summary, AKT signaling could be a promising therapeutical approach for patients with bone metastases of solid tumors.

Knockdown of AKT3 Activates HER2 and DDR Kinases in Bone-Seeking Breast Cancer Cells, Promotes Metastasis In Vivo and Attenuates the TGFß/CTGF Axis.

Bone metastases frequently occur in breast cancer patients and lack appropriate treatment options. Hence, understanding the molecular mechanisms involved in the multistep process of breast cancer bone metastasis and tumor-induced osteolysis is of paramount interest. The serine/threonine kinase AKT plays a crucial role in breast cancer bone metastasis but the effect of individual AKT isoforms remains unclear. Therefore, AKT isoform-specific knockdowns were generated on the bone-seeking MDA-MB-231 BO subline and the effect on proliferation, migration, invasion, and chemotaxis was analyzed by live-cell imaging. Kinome profiling and Western blot analysis of the TGFß/CTGF axis were conducted and metastasis was evaluated by intracardiac inoculation of tumor cells into NOD scid gamma (NSG) mice. MDA-MB-231 BO cells exhibited an elevated AKT3 kinase activity in vitro and responded to combined treatment with AKT- and mTOR-inhibitors. Knockdown of AKT3 significantly increased migration, invasion, and chemotaxis in vitro and metastasis to bone but did not significantly enhance osteolysis. Furthermore, knockdown of AKT3 increased the activity and phosphorylation of pro-metastatic HER2 and DDR1/2 but lowered protein levels of CTGF after TGFß-stimulation, an axis involved in tumor-induced osteolysis. We demonstrated that AKT3 plays a crucial role in bone-seeking breast cancer cells by promoting metastatic potential without facilitating tumor-induced osteolysis.

High Sensitivity of Circulating Tumor Cells Derived from a Colorectal Cancer Patient for Dual Inhibition with AKT and mTOR Inhibitors.

Circulating tumor cells (CTCs) are cells shed from the primary tumor into the bloodstream. While many studies on solid tumor cells exist, data on CTCs are scarce. The mortality of cancer is mostly associated with metastasis and recent research identified CTCs as initiators of metastasis. The PI3K/AKT/mTOR signaling pathway is an intracellular pathway that regulates essential functions including protein biosynthesis, cell growth, cell cycle control, survival and migration. Importantly, activating oncogenic mutations and amplifications in this pathway are frequently observed in a wide variety of cancer entities, underlining the significance of this signaling pathway. In this study, we analyzed the functional role of the PI3K/AKT/mTOR signaling pathway in the CTC-MCC-41 line, derived from a patient with metastatic colorectal cancer. One striking finding in our study was the strong sensitivity of this CTC line against AKT inhibition using MK2206 and mTOR inhibition using RAD001 within the nanomolar range. This suggests that therapies targeting AKT and mTOR could have been beneficial for the patient from which the CTC line was isolated. Additionally, a dual targeting approach of AKT/mTOR inside the PI3K/AKT/mTOR signaling pathway in the colorectal CTCs showed synergistic effects in vitro. Depending on the phenotypical behavior of CTC-MCC-41 in cell culture (adherent vs. suspension), we identified altered phosphorylation levels inside the PI3K/AKT/mTOR pathway. We observed a downregulation of the PI3K/AKT/mTOR signaling pathway, but not of the RAS/RAF/MAPK pathway, in CTCs growing in suspension in comparison to adherent CTCs. Our results highlight distinct functions of AKT isoforms in CTC-MCC-41 cells with respect to cell proliferation. Knockdown of AKT1 and AKT2 leads to significantly impaired proliferation of CTC-MCC-41 cells in vitro. Therefore, our data demonstrate that the PI3K/AKT/mTOR signaling pathway plays a key role in the proliferation of CTC-MCC-41.

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

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 ß-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.