Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in cancer. By applying mass spectroscopy-based sequencing and reverse-phase protein arrays to 547 human breast cancers and 41 cell lines, we determined the subtype specificity and signaling effects of PIK3CA, AKT, and PTEN mutations and the effects of PIK3CA mutations on responsiveness to PI3K inhibition in vitro and on outcome after adjuvant tamoxifen. PIK3CA mutations were more common in hormone receptor-positive (34.5%) and HER2-positive (22.7%) than in basal-like tumors (8.3%). AKT1 (1.4%) and PTEN (2.3%) mutations were restricted to hormone receptor-positive cancers. Unlike AKT1 mutations that were absent from cell lines, PIK3CA (39%) and PTEN (20%) mutations were more common in cell lines than tumors, suggesting a selection for these but not AKT1 mutations during adaptation to culture. PIK3CA mutations did not have a significant effect on outcome after adjuvant tamoxifen therapy in 157 hormone receptor-positive breast cancer patients. PIK3CA mutations, in comparison with PTEN loss and AKT1 mutations, were associated with significantly less and inconsistent activation of AKT and of downstream PI3K/AKT signaling in tumors and cell lines. PTEN loss and PIK3CA mutation were frequently concordant, suggesting different contributions to pathophysiology. PTEN loss rendered cells significantly more sensitive to growth inhibition by the PI3K inhibitor LY294002 than did PIK3CA mutations. Thus, PI3K pathway aberrations likely play a distinct role in the pathogenesis of different breast cancer subtypes. The specific aberration present may have implications for the selection of PI3K-targeted therapies in hormone receptor-positive breast cancer.

/pdf/an-integrative-genomic-and-proteomic-analysis-of-pik3ca-pten-50w11rlrov.pdf

An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer.

For the past 30 years, improvements in the survival of patients with osteosarcoma have been mostly incremental. Despite evidence of genomic instability and a high frequency of chromothripsis and kataegis, osteosarcomas carry few recurrent targetable mutations, and trials of targeted agents have been generally disappointing. Bone has a highly specialized immune environment and many immune signalling pathways are important in bone homeostasis. The success of the innate immune stimulant mifamurtide in the adjuvant treatment of non-metastatic osteosarcoma suggests that newer immune-based treatments, such as immune checkpoint inhibitors, may substantially improve disease outcome.

Translational biology of osteosarcoma

The conserved serine/threonine kinase mTOR (the mammalian target of rapamycin), a downstream effector of the PI3K/AKT pathway, forms two distinct multiprotein complexes: mTORC1 and mTORC2 mTORC1 is sensitive to rapamycin, activates S6K1 and 4EBP1, which are involved in mRNA translation It is activated by diverse stimuli, such as growth factors, nutrients, energy and stress signals, and essential signalling pathways, such as PI3K, MAPK and AMPK, in order to control cell growth, proliferation and survival mTORC2 is considered resistant to rapamycin and is generally insensitive to nutrients and energy signals It activates PKC-α and AKT and regulates the actin cytoskeleton Deregulation of multiple elements of the mTOR pathway (PI3K amplification/mutation, PTEN loss of function, AKT overexpression, and S6K1, 4EBP1 and eIF4E overexpression) has been reported in many types of cancers, particularly in melanoma, where alterations in major components of the mTOR pathway were reported to have significant effects on tumour progression Therefore, mTOR is an appealing therapeutic target and mTOR inhibitors, including the rapamycin analogues deforolimus, everolimus and temsirolimus, are submitted to clinical trials for treating multiple cancers, alone or in combination with inhibitors of other pathways Importantly, temsirolimus and everolimus were recently approved by the FDA for the treatment of renal cell carcinoma, PNET and giant cell astrocytoma Small molecules that inhibit mTOR kinase activity and dual PI3K-mTOR inhibitors are also being developed In this review, we aim to survey relevant research, the molecular mechanisms of signalling, including upstream activation and downstream effectors, and the role of mTOR in cancer, mainly in melanoma

https://www.mdpi.com/1422-0067/13/2/1886/pdf

The mTOR signalling pathway in human cancer.

As the most commonly occurring cancer in women worldwide, breast cancer poses a formidable public health challenge on a global scale. Breast cancer consists of a group of biologically and molecularly heterogeneous diseases originated from the breast. While the risk factors associated with this cancer varies with respect to other cancers, genetic predisposition, most notably mutations in BRCA1 or BRCA2 gene, is an important causative factor for this malignancy. Breast cancers can begin in different areas of the breast, such as the ducts, the lobules, or the tissue in between. Within the large group of diverse breast carcinomas, there are various denoted types of breast cancer based on their invasiveness relative to the primary tumor sites. It is important to distinguish between the various subtypes because they have different prognoses and treatment implications. As there are remarkable parallels between normal development and breast cancer progression at the molecular level, it has been postulated that breast cancer may be derived from mammary cancer stem cells. Normal breast development and mammary stem cells are regulated by several signaling pathways, such as estrogen receptors (ERs), HER2, and Wnt/β-catenin signaling pathways, which control stem cell proliferation, cell death, cell differentiation, and cell motility. Furthermore, emerging evidence indicates that epigenetic regulations and noncoding RNAs may play important roles in breast cancer development and may contribute to the heterogeneity and metastatic aspects of breast cancer, especially for triple-negative breast cancer. This review provides a comprehensive survey of the molecular, cellular and genetic aspects of breast cancer.

Breast cancer development and progression: Risk factors, cancer stem cells, signaling pathways, genomics, and molecular pathogenesis.

Recent medical advances have improved the understanding, diagnosis, and treatment of paraneoplastic syndromes. These disorders arise from tumor secretion of hormones, peptides, or cytokines or from immune cross-reactivity between malignant and normal tissues. Paraneoplastic syndromes may affect diverse organ systems, most notably the endocrine, neurologic, dermatologic, rheumatologic, and hematologic systems. The most commonly associated malignancies include small cell lung cancer, breast cancer, gynecologic tumors, and hematologic malignancies. In some instances, the timely diagnosis of these conditions may lead to detection of an otherwise clinically occult tumor at an early and highly treatable stage. Because paraneoplastic syndromes often cause considerable morbidity, effective treatment can improve patient quality of life, enhance the delivery of cancer therapy, and prolong survival. Treatments include addressing the underlying malignancy, immunosuppression (for neurologic, dermatologic, and rheumatologic paraneoplastic syndromes), and correction of electrolyte and hormonal derangements (for endocrine paraneoplastic syndromes). This review focuses on the diagnosis and treatment of paraneoplastic syndromes, with emphasis on those most frequently encountered clinically. Initial literature searches for this review were conducted using PubMed and the keyword paraneoplastic in conjunction with keywords such as malignancy, SIADH, and limbic encephalitis, depending on the particular topic. Date limitations typically were not used, but preference was given to recent articles when possible.

https://www.mayoclinicproceedings.org/article/S0025-6196(11)60214-0/pdf

Paraneoplastic Syndromes: An Approach to Diagnosis and Treatment

This study was designed to investigate the mammography and ultrasound findings of triple-negative breast cancer and to compare the results with characteristics of ER-positive/PR-negative/HER2-negative breast cancer and ER-negative/PR-negative/HER2-positive breast cancer. From January 2007 to October 2008, mammography and ultrasound findings of 245 patients with pathologically confirmed triple-negative (n = 87), ER-positive/PR-negative/HER2-negative (n = 93) or ER-negative/PR-negative/HER2-positive breast cancers (n = 65) were retrospectively reviewed. We also reviewed pathological reports for information on the histological type, histological grade and the status of the biological markers. Triple-negative breast cancers showed a high histological grade. On mammography, triple-negative breast cancers usually presented with a mass (43/87, 49%) or with focal asymmetry (19/87, 22%), and were less associated with calcifications. On ultrasound, the cancers were less frequently seen as non-mass lesions (12/87, 14%), more likely to have circumscribed margins (43/75, 57%), were markedly hypoechoic (36/75, 57%) and less likely to show posterior shadowing (4/75, 5%). Among the three types of breast cancers, ER-negative/PR-negative/HER2-positive breast cancers most commonly had associated calcifications (52/65, 79%) on mammography and were depicted as non-mass lesions (21/65, 32%) on ultrasound. Our results suggest that the imaging findings might be useful in diagnosing triple-negative breast cancer.

Triple-negative breast cancer: correlation between imaging and pathological findings

Response to neoadjuvant chemotherapy is a significant prognostic factor for osteosarcoma; however, this information can be determined only after surgical resection. If we could predict histologic response before surgery, it might be helpful for the planning of surgeries and tailoring of treatment. We evaluated the usefulness of 18 F-FDG PET for this purpose. Methods: A total of 70 consecutive patients with a high-grade osteosarcoma treated at our institute were prospectively enrolled. All patients underwent 18 F-FDG PET and MRI before and after neoadjuvant chemotherapy. We analyzed the predictive values of 5 parameters, namely, maximum standardized uptake values (SUVs), before and after (SUV2) chemotherapy, SUV change ratio, tumor volumechangeratio,andmetabolicvolumechangeratio(MVCR) in terms of their abilities to discriminate responders from nonresponders. Results:PatientswithanSUV2oflessthanorequalto 2showed agood histologic response, andpatients withan SUV2 of greater than 5 showed a poor histologic response. The histologic response of a patient with an intermediate SUV2 (2 , SUV2 # 5) was found to be predictable using MVCR. A patient with an MVCR of less than 0.65 is likely to be a good responder, whereas a patient with an MVCR of greater than or equal to 0.65 is likely to be a poor responder. According to our model, the predictive values for good responders and poor responders were 97% (31/32) and 95% (36/38), respectively. Conclusion: We found that combined information on 18F-FDG PET and MRI scans, acquired before and after chemotherapy, could be used to predict histologic response to neoadjuvant chemotherapy in

http://jnm.snmjournals.org/content/50/9/1435.full.pdf

Prediction model of chemotherapy response in osteosarcoma by 18F-FDG PET and MRI.

Rapamycin and its analogues are currently being tested in clinical trials as novel–targeted anticancer agents. Pre-clinical studies that used breast cancer cell lines have suggested that p-Akt or p-S6K1 expressing tumors, as well as PTEN negative tumors, were sensitive to rapamycin. The aims of this study were to determine the proportion of breast cancer that could be candidates for rapamycin treatment and to elucidate the clinicopathologic characteristics and prognosis of potentially rapamycin-sensitive tumors. We evaluated the expressions of PTEN, p-Akt and p-S6K1 by performing immunohistochemistry in 122 breast cancer tissues. We analyzed the association of the expression of these proteins with the cliniopathologic variables and the disease-free survival. PTEN negative tumors, p-Akt expressing tumors and p-S6K1 expressing tumors constituted 4.1% (5/122), 41.0% (50/122), and 36.1% (44/122) of the total tumors, respectively. The proportion of tumors that met the criteria of rapamycin sensitivity was 54.9% (67/122). We could not find any significant correlation between the expression of these proteins and the other prognostic factors. However, the prognosis of tumors with a p-S6K1 expression was significantly worse than that of the p-S6K1 negative tumors. Based on the status of the PTEN, p-Akt and p-S6K1 expressions as predictors of rapamycin sensitivity, this study suggested that over 50% of breast cancer patients could be potential candidates for rapamycin treatment. In addition, the p-S6K1 expression may constitute an independent prognostic factor for disease-free survival.

Activation of the mTOR signaling pathway in breast cancer and its correlation with the clinicopathologic variables

Background

The receptor activator of nuclear factor κB ligand (RANKL/TNFSF11) is expressed in metastatic bone cancer cells and has been suggested to play a key role in cell migration and metastatic behavior. We determined whether RANKL expression is correlated to clinical behavior of localized, high-grade osteosarcoma.



Patients and methods

This retrospective, immunohistochemical study was performed using materials obtained from 40 patients treated at Korea Cancer Center Hospital between 1995 and 2007. Prechemotherapy biopsy samples were stained for RANKL and correlations between RANKL expression and clinical characteristics and outcomes were evaluated. Staining was interpreted in a semiquantitative manner using an intensity based scoring system.



Results

Thirty cases (75.0%) stained positively for RANKL; 15 (50.0%) had a high RANKL score (≥ 4) and the other 15 a low RANKL score (≤3). RANKL expression and RANKL scores were not related to age, sex, tumor location, tumor volume, or pathologic subtype. However, RANKL expression was related to a poor response to preoperative chemotherapy (P = 0.03) and a high RANKL score was associated with inferior survival. The 5-year event-free survival of patients with RANKL score ≥4 was 17.8 ± 10.5%, which was far worse than those with RANKL scores 1–3 or 0 (50.0 ± 15.8%, 56.0 ± 13.7%, respectively, P = 0.02).



Conclusions

The RANKL–RANK–OPG axis might be a promising target for the treatment of osteosarcoma, but further studies are needed to verify our data in a larger cohort. Pediatr Blood Cancer 2011;56:738–743. © 2010 Wiley-Liss, Inc.

RANKL expression is related to treatment outcome of patients with localized, high-grade osteosarcoma.

Ezrin, a cytoskeleton linker protein, has been reported to be involved in the metastasis of solid tumors in animal models and patients in small clinical studies. We analyzed the relationship between immunohistochemical expression of ezrin and the prognosis of osteosarcoma. We retrospectively identified 64 patients with Stage IIB osteosarcomas between 1995 and 2000. Tissue microarrays were constructed from incisional biopsy specimens and immunohistochemical staining was performed. Ezrin expression and other clinicopathologic variables such as age, gender, pathologic subtype, tumor size and location, and histologic response were compared with outcomes. The minimum followup was 12 months (mean, 78.2 months; range, 12-137 months). Twenty-three of 64 patients (35.9%) showed late distant metastasis; 33 of 64 patients (51.6%) showed expression of ezrin, and of these 33 patients, 22 (66.7%) had distant metastasis develop. Multivariate analysis revealed histologic response to preoperative chemotherapy and expression of ezrin predicted disease-free survival. Expression of ezrin in osteosarcoma biopsy specimens is promising as a marker to predict outcome in patients with osteosarcoma.

Min Suk Kim

Papers

Triple-negative breast cancer: correlation between imaging and pathological findings

Prediction model of chemotherapy response in osteosarcoma by 18F-FDG PET and MRI.

Activation of the mTOR signaling pathway in breast cancer and its correlation with the clinicopathologic variables

RANKL expression is related to treatment outcome of patients with localized, high-grade osteosarcoma.

Ezrin expression predicts survival in stage IIB osteosarcomas.