Biology of primary breast cancer in older women beyond routine biomarkers.

PURPOSE: There are numerous biomarkers which may have potential predictive and prognostic significance in breast cancer. This is extremely important in older adults, who may opt for less aggressive therapy. This work outlines the literature on biological assessment outside of standard biomarkers (defined as ER, PgR, HER2, Ki67) in women ≥ 65 years with primary operable invasive breast cancer, to determine which additional biomarkers are relevant to outcome in older women. METHODS: Medline and Embase databases were searched. Studies were eligible if included ≥ 50 patients aged ≥ 65 years; stratified results by age; measured a biomarker outside of standard assay and reported patient data. RESULTS: A total of 12 studies were appraised involving 5000 patients, measuring 28 biomarkers. The studies were extremely varied in methodology and outcome but three themes emerged: 1. Differences in biomarker expression between younger and older women, indicating that breast cancer in older women is generally less aggressive compared to younger women; 2. Relationship of biomarker expression with survival, suggesting biomarkers which may exclusively predict response to primary treatment in older women; 3. Association of biomarker with chemotherapy, suggesting that older patients should not be declined chemotherapy based on age alone. CONCLUSION: There is evidence to support further investigation of B-cell lymphoma (BCL2), liver kinase (LK)B1, epidermal growth factor receptor (EGFR), cytoplasmic cyclin-E, mucin (MUC)1 and cytokeratins (CKs) as potential predictive or prognostic markers in older women with breast cancer undergoing surgery. Studies exploring these biomarkers in larger cohorts and in women undergoing non-operative therapies are required.

Patterns of biomarker expression in patients treated with primary endocrine therapy - a unique insight using core needle biopsy tissue microarray.

PURPOSE: Prediction of response to primary endocrine therapy (PET) in older women is based on measurement of oestrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor (HER)-2. This study uses a unique method for construction of core needle biopsy (CNB) tissue microarray (TMA), to correlate expression of a panel of 17 biomarkers with clinical outcome, in patients receiving PET. METHODS: Over 37 years (1973-2010), 1758 older (≥ 70 years) women with operable primary breast cancer were managed in a single institution. Of these, 693 had sufficient good-quality CNB to construct TMA, of which 334 had ER-positive tumours treated by PET with a minimum of 6-month follow-up. A panel of biomarkers was measured by immunohistochemistry (ER, PgR, HER2, Ki-67, p53, CK5/6, CK 7/8, EGFR, BCL-2, MUC1, VEGF, LKB1, BRCA1, HER3, HER4, PTEN and AIB1). Expression of each biomarker was dichotomised into 'low' or 'high' based on breast cancer-specific survival (BCSS). RESULTS: From the panel of biomarkers, multivariate analysis showed: High ER (p = 0.003) and PgR (p = 0.002) were associated with clinical benefit of PET at 6 months, as opposed to progressive disease. High ER (p = 0.0023), PgR (p < 0.001) and BCL-2 (p = 0.043) and low LKB1 (p = 0.022) were associated with longer time to progression. High PgR (p < 0.001) and low MUC1 (p = 0.021) were associated with better BCSS. Expression of other biomarkers did not show any significant correlation. CONCLUSIONS: In addition to ER and PgR; MUC1, BCL-2 and LKB1 are important in determining the outcome of PET in this cohort.

The OPTIMIZE patient- and family-centered, primary care-based deprescribing intervention for older adults with dementia or mild cognitive impairment and multiple chronic conditions: study protocol for a pragmatic cluster randomized controlled trial.

BACKGROUND: Most individuals with dementia or mild cognitive impairment (MCI) have multiple chronic conditions (MCC). The combination leads to multiple medications and complex medication regimens and is associated with increased risk for significant treatment burden, adverse drug events, cognitive changes, hospitalization, and mortality. Optimizing medications through deprescribing (the process of reducing or stopping the use of inappropriate medications or medications unlikely to be beneficial) may improve outcomes for MCC patients with dementia or MCI. METHODS: With input from patients, family members, and clinicians, we developed and piloted a patient-centered, pragmatic intervention (OPTIMIZE) to educate and activate patients, family members, and primary care clinicians about deprescribing as part of optimal medication management for older adults with dementia or MCI and MCC. The clinic-based intervention targets patients on 5 or more medications, their family members, and their primary care clinicians using a pragmatic, cluster-randomized design at Kaiser Permanente Colorado. The intervention has two components: a patient/ family component focused on education and activation about the potential value of deprescribing, and a clinician component focused on increasing clinician awareness about options and processes for deprescribing. Primary outcomes are total number of chronic medications and total number of potentially inappropriate medications (PIMs). We estimate that approximately 2400 patients across 9 clinics will receive the intervention. A comparable number of patients from 9 other clinics will serve as wait-list controls. We have > 80% power to detect an average decrease of - 0.70 (< 1 medication). Secondary outcomes include the number of PIM starts, dose reductions for selected PIMs (benzodiazepines, opiates, and antipsychotics), rates of adverse drug events (falls, hemorrhagic events, and hypoglycemic events), ability to perform activities of daily living, and skilled nursing facility, hospital, and emergency department admissions. DISCUSSION: The OPTIMIZE trial will examine whether a primary care-based, patient- and family-centered intervention educating patients, family members, and clinicians about deprescribing reduces numbers of chronic medications and PIMs for older adults with dementia or MCI and MCC. TRIAL REGISTRATION: NCT03984396. Registered on 13 June 2019.

The Use of Figurative Language to Describe Frailty in Older Adults.

INTRODUCTION: Frailty affects 15% of non-institutionalized older adults in the United States, yet confusion remains in defining and, in turn, assessing frailty. Figurative language, such as metaphor, can help to explain difficult scientific concepts and to form new theories. We aimed to examine the use of figurative language to describe frailty and to identify themes in the way figurative expressions are used. Understanding how frailty is described figuratively may offer insights for developing useful communication approaches in research settings. METHODS: We performed a comprehensive review of editorials in the scientific literature to explore figurative language used to describe frailty in older adults. We categorized themes among the figurative expressions, which may help to inform how to effectively communicate about frailty. RESULTS: We found 24 editorials containing 32 figurative expressions. The figurative expressions conceptualized frailty in six ways: 1) a complex, multifaceted concept; 2) an important issue in health and medicine; 3) indicative of something that is failing or faulty; 4) indicative of fragility; 5) representative of vulnerable, ignored persons; and 6) an opportunity for self-awareness and reflection. DISCUSSION: Our review highlights the heterogeneity in depictions of frailty, which is consonant with the lack of a standardized definition of frailty. We also found a novel aspect to the concept of frailty, which merits attention: frailty characterized as an opportunity for self-awareness and reflection. Figurative language, which often juxtaposes familiar with challenging, complex concepts, can offer insights on issues in frailty research and holds potential as a tool for researchers to improve communication about this important and debated medical condition.

The significance of tumour microarchitectural features in breast cancer prognosis: a digital image analysis.

BACKGROUND: As only a minor portion of the information present in histological sections is accessible by eye, recognition and quantification of complex patterns and relationships among constituents relies on digital image analysis. In this study, our working hypothesis was that, with the application of digital image analysis technology, visually unquantifiable breast cancer microarchitectural features can be rigorously assessed and tested as prognostic parameters for invasive breast carcinoma of no special type. METHODS: Digital image analysis was performed using public domain software (ImageJ) on tissue microarrays from a cohort of 696 patients, and validated with a commercial platform (Visiopharm). Quantified features included elements defining tumour microarchitecture, with emphasis on the extent of tumour-stroma interface. The differential prognostic impact of tumour nest microarchitecture in the four immunohistochemical surrogates for molecular classification was analysed. Prognostic parameters included axillary lymph node status, breast cancer-specific survival, and time to distant metastasis. Associations of each feature with prognostic parameters were assessed using logistic regression and Cox proportional models adjusting for age at diagnosis, grade, and tumour size. RESULTS: An arrangement in numerous small nests was associated with axillary lymph node involvement. The association was stronger in luminal tumours (odds ratio (OR) = 1.39, p = 0.003 for a 1-SD increase in nest number, OR = 0.75, p = 0.006 for mean nest area). Nest number was also associated with survival (hazard ratio (HR) = 1.15, p = 0.027), but total nest perimeter was the parameter most significantly associated with survival in luminal tumours (HR = 1.26, p = 0.005). In the relatively small cohort of triple-negative tumours, mean circularity showed association with time to distant metastasis (HR = 1.71, p = 0.027) and survival (HR = 1.8, p = 0.02). CONCLUSIONS: We propose that tumour arrangement in few large nests indicates a decreased metastatic potential. By contrast, organisation in numerous small nests provides the tumour with increased metastatic potential to regional lymph nodes. An outstretched pattern in small nests bestows tumours with a tendency for decreased breast cancer-specific survival. Although further validation studies are required before the argument for routine quantification of microarchitectural features is established, our approach is consistent with the demand for cost-effective methods for triaging breast cancer patients that are more likely to benefit from chemotherapy.

Modeling electrochromic poly-dioxythiophene-containing materials through TDDFT.

A DFT/TDDFT model was developed to predict the chemical properties for three colored to nearly transmissive electrochromic polymers synthesized by the John Reynolds's group. Using a functional-basis set pairing of mPW1PBE/cc-PVDZ along with the conductor polarizable calculation model (CPCM), simulated neutral spectra showed a strong correlation to the experimental UV-Vis data where the largest absolute peak maximum difference was 14 nm. Frontier molecular orbitals, electronic transitions, and ground-state geometries of these systems were evaluated to provide further information about the oxidative process the polymers undergo. Here we report the first colorimetric model using this level of theory.

Current trials to reduce surgical intervention in ductal carcinoma in situ of the breast: Critical review.

The high proportion of ductal carcinoma in situ (DCIS) presented in mammographic screening and the relatively low risk of progression to invasive disease have raised questions related to overtreatment. Following a review of current DCIS management protocols a more conservative approach has been suggested. Clinical trials have been introduced to evaluate the option of avoiding surgical intervention in a proportion of patients with DCIS defined as "low-risk" using certain clinicopathological criteria. These trials can potentially provide evidence-based models of active surveillance (with or without endocrine therapy) as a future management approach. Despite the undisputable fact of our need to address the obvious overtreatment of screen-detected DCIS, some important questions need to be considered regarding these trials including the eligibility criteria and definition of risk, the proportion of patient eligible for inclusion, and the length of time required for proper analysis of the trials' outcome in view of the long-term natural history of DCIS progression particularly the low-risk group. These factors can potentially affect the practicality and future impact of such trials. This review provides critical analysis of current DCIS management trials and highlights critical issues related to their practicality and the expected outcome.

Equivalence of BCSH and WHO diagnostic criteria for ET.

This corrects the article DOI: 10.1038/leu.2016.318.

The effect of chronic ammonia exposure on acute-phase proteins, immunoglobulin, and cytokines in laying hens.

Ammonia (NH3) is a potential health hazard to both humans and animals, causing local and systemic low-grade inflammation based on its levels and exposure durations. The objective of this study was to examine the effects of 45 wk of exposure to 30 ppm NH3 on the concentrations of acute-phase proteins, immunoglobulins, and cytokines in laying hens. At 18 wk of age, a group of Hy-Line W-36 hens was randomly assigned to 4-hen cages. These cages were evenly divided between 2 environmentally controlled chambers. At 25 wk of age, one chamber was maintained continuously with fresh air (NH3 < 5 ppm; control group) and the other one was injected with NH3 and controlled at 30 ppm (NH3 group) for 45 wk. At 70 wk of age, blood and spleen samples (n = 8 per treatment) were collected for analyses of immunological parameters. No significant differences were observed in plasma levels of albumin, complement components (C)-3 and C-4, immunoglobulin (Ig)M, IgA and IgG, interleukin (IL)-6, IL-10, or interferon gamma in the NH3 group compared to control group. Compared to control hens, NH3 exposed hens had higher plasma levels of α-1-acid glycoprotein (24%) and tumor necrosis factor alpha (54%) and higher mRNA expression of IL-1ß (47%) and IL-6 (62.5%) in the spleen. These results indicated that hens may have the capability to adapt to chronic effects of moderate levels of NH3. Future studies should explore acute effects of NH3 at higher levels on hen health and welfare.

Tumour cell membrane laminin expression is associated with basal-like phenotype and poor survival in Nigerian breast cancer.

INTRODUCTION: Laminin is a glycoprotein with diverse functions in carcinogenesis including cell proliferation, invasion, metastases and epithelial-mesenchymal transition (EMT). In breast cancer (BC) laminin expression is speculated to be associated with unfavourable clinicopathological and molecular characteristics. We hypothesize that laminin expression would contributed to the aggressive nature of basal like and triple negative BC phenotype observed in Black women. METHODS: The expression of laminin was determined in a well-characterised Nigerian cohort of 255 BC using tissue microarray and immunohistochemistry. Laminin expression was compared with clinical, pathological and survival characteristics. RESULTS: Laminin was expressed in 146 (57.3%) cases and significantly correlated with younger age at diagnosis (p=0.005), premenopausal status (p=0.003), expression of EGFR (p=0.002), ID4 and MTA1, basal cytokeratin 5/6, p53, and triple negative tumours (all p<0.001). In addition, there was an inverse association of laminin expression with E-cadherin (p=0.03), ER and PgR (all p<0.001) and a trend with BRCA1 (p=0.05). Univariate survival analysis showed tumours positive for laminin had significantly poorer breast cancer specific survival (BCSS, p=0.009) and disease free interval (p=0.03), but not associated in Cox multivariate analysis. CONCLUSION: This study demonstrates that laminin expression may have important roles in the aggressive nature observed in the basal-like and triple negative molecular subtype of Nigerian BC women.

Impact of intratumoural heterogeneity on the assessment of Ki67 expression in breast cancer.

In breast cancer (BC), the prognostic value of Ki67 expression is well-documented. Intratumoural heterogeneity (ITH) of Ki67 expression is amongst the several technical issues behind the lag of its inclusion into BC prognostic work-up. The immunohistochemical (IHC) expression of anti-Ki67 antibody (MIB1 clone) was assessed in four full-face (FF) sections from different primary tumour blocks and their matched axillary nodal (LN) metastases in a series of 55 BC. Assessment was made using the highest expression hot spots (HS), lowest expression (LS), and overall/average expression scores (AS) in each section. Heterogeneity score (Hes), co-efficient of variation, and correlation co-efficient were used to assess the levels of Ki67 ITH. Ki67 HS, LS, and AS scores were highly variable within the same section and between different sections of the primary tumour, with maximal variation observed in the LS (P < 0.001). The least variability between the different slides was observed with HS scoring. Although the associations between Ki67 and clinicopathological and molecular variables were similar when using HS or AS, the best correlation between AS and HS was observed in tumours with high Ki67 expression only. Ki67 expression in LN deposits was less heterogeneous than in the primary tumours and was perfectly correlated with the HS Ki67 expression in the primary tumour sections (r = 0.98, P < 0.001). In conclusion, assessment of Ki67 expression using HS scoring method on a full-face BC tissue section can represent the primary tumour growth fraction that is likely to metastasise. The association between Ki67 expression pattern in the LN metastasis and the HS in the primary tumour may reflect the temporal heterogeneity through clonal expansion.

JAK2V617F mediates resistance to DNA damage-induced apoptosis by modulating FOXO3A localization and Bcl-xL deamidation.

The JAK2V617F mutation is found in most patients with a myeloproliferative neoplasm (MPN). This gain-of-function mutation dysregulates cytokine signaling and is associated with increased accumulation of DNA damage, a process likely to drive disease evolution. JAK2V617F inhibits NHE-1 upregulation in response to DNA damage and consequently represses Bcl-xL deamidation and apoptosis, thus giving rise to inappropriate cell survival. However, the mechanism whereby NHE-1 expression is inhibited by JAK2V617F is unknown. In this study, we demonstrate that the accumulation of reactive oxygen species (ROS) in cells expressing JAK2V617F compromises the NHE-1/Bcl-xL deamidation pathway by repressing NHE-1 upregulation in response to DNA damage. In JAK2V617F-positive cells, increased ROS levels results from aberrant PI3K signaling, which decreases nuclear localization of FOXO3A and decreases catalase expression. Furthermore, when compared with autologous control erythroblasts, clonally derived JAK2V617F-positive erythroblasts from MPN patients displayed increased ROS levels and reduced nuclear FOXO3A. However, in hematopoietic stem cells (HSCs), FOXO3A is largely localized within the nuclei despite the presence of JAK2V617F mutation, suggesting that JAK2-FOXO signaling has a different effect on progenitors compared with stem cells. Inactivation of FOXO proteins and elevation of intracellular ROS are characteristics common to many cancers, and hence these findings are likely to be of relevance beyond the MPN field.

Effect of dietary fat concentration from condensed corn distillers' solubles, during the growing phase, on beef cattle performance, carcass traits, digestibility, and ruminal metabolism.

The objectives of this study were to determine the effect of fat concentration from corn distillers' solubles (CDS), fed during the growing phase, on DMI, gain, carcass traits, digestibility, ruminal metabolism, and methane emissions of steers. In Exp. 1, 40 steers (age = 136 ± 20 d; BW = 185 ± 11 kg) were randomly allotted to 1 of 5 dietary treatments: 1) a cosrn-based gro\wing diet (CNT), 2) 0% CDS, 3) 10% CDS, 4) 19% CDS, or 5) 27% CDS. Diets 2 through 5 included coproducts (corn gluten feed and soybean hulls) and were formulated to achieve fat concentrations of 3, 5, 7, and 9%, respectively. Diets were fed once daily for 106 d (growing phase). All steers were fed a corn-based diet from d 107 to 196. Contrasts were used to examine 1) the difference between CNT and 10% CDS and 2) linear and quadratic effects of CDS inclusion. During the growing phase, steers fed CNT had increased ( < 0.01) ADG and G:F compared with steers fed 10% CDS. Increasing CDS inclusion increased (linear, ≤ 0.02) ADG and G:F. Overall, steers fed CNT had increased ( < 0.01) ADG compared with steers fed 10% CDS, but increasing CDS inclusion had no effect ( = 0.19) on overall ADG. Overall DMI and G:F were not different ( ≥ 0.16) in any contrast. There was a trend (Linear; = 0.08) for ultrasound marbling at d 196 to increase as CDS inclusion increased; however, there were no effects ( ≥ 0.20) of treatment on carcass marbling or quality grade. In Exp. 2, 5 steers (BW = 335 ± 56 kg) were fed Exp. 1 diets for ad libitum intakes in a 5 × 5 Latin square design. Apparent DM digestibility increased (linear, = 0.02) with increasing dietary CDS inclusion. Steers fed CNT had greater ( = 0.01) DM digestibility than those fed 10% CDS. Fat digestibility increased (linear, < 0.01) in steers with increasing CDS, but NDF and ADF digestibility were not affected ( ≥ 0.17) by treatment. Similarly, ruminal pH and VFA concentrations were not affected ( ≥ 0.13). Also, there was no difference ( ≥ 0.37) in ruminal methane emissions (g/h). In conclusion, feeding corn during the growing phase increased overall ADG compared with 10% CDS coproduct-based diet but did not affect carcass traits or methane production. Increasing dietary fat inclusion from CDS in coproduct-based diets linearly increased DM and fat digestibility and predicted marbling scores via ultrasound but did not affect marbling at slaughter, NDF digestibility, propionate, or methane production.

KPNA2 is a nuclear export protein that contributes to aberrant localisation of key proteins and poor prognosis of breast cancer.

BACKGROUND: It is recognised that modulations of the nuclear import of macromolecules have a role in changing cellular phenotypes and carcinogenesis. We and others have noticed that aberrant subcellular localisation of DNA damage response (DDR) proteins in breast cancer (BC) is associated with loss-of-function phenotype. This study aims to investigate the biological and clinical significance of the nucleocytoplasmic transport protein karyopherin α-2 (KPNA2), and its role in controlling DDR proteins subcellular localisation in BC. METHODS: A large (n=1494) and well-characterised series of early-stage invasive BC with a long-term follow-up was assessed for KPNA2 protein by using immunohistochemistry. RESULTS: KPNA2 expression was associated with the subcellular localisation of key DDR proteins that showed cytoplasmic expression including BRCA1, RAD51, SMC6L1, γH2AX, BARD1, UBC9, PIAS1 and CHK1. High level of KPNA2 was associated not only with cytoplasmic localisation of these proteins but also with their low/negative nuclear expression. Positive KPNA2 expression was associated with negative oestrogen receptor and triple-negative phenotype. Survival analysis showed that KPNA2 was associated with poor outcome (P<0.0001), but this effect was not independent of other prognostic variables. CONCLUSIONS: This study provides further evidence for the complexity of DDR mechanism in BC, and that KNPA2 has a role in the aberrant subcellular localisation of DDR proteins with subsequent impaired function.

Markers of progression in early-stage invasive breast cancer: a predictive immunohistochemical panel algorithm for distant recurrence risk stratification.

Accurate distant metastasis (DM) prediction is critical for risk stratification and effective treatment decisions in breast cancer (BC). Many prognostic markers/models based on tissue marker studies are continually emerging using conventional statistical approaches analysing complex/dimensional data association with DM/poor prognosis. However, few of them have fulfilled satisfactory evidences for clinical application. This study aimed at building DM risk assessment algorithm for BC patients. A well-characterised series of early invasive primary operable BC (n = 1902), with immunohistochemical expression of a panel of biomarkers (n = 31) formed the material of this study. Decision tree algorithm was computed using WEKA software, utilising quantitative biomarkers' expression and the absence/presence of distant metastases. Fifteen biomarkers were significantly associated with DM, with six temporal subgroups characterised based on time to development of DM ranging from <1 to >15 years of follow-up. Of these 15 biomarkers, 10 had a significant expression pattern where Ki67LI, HER2, p53, N-cadherin, P-cadherin, PIK3CA and TOMM34 showed significantly higher expressions with earlier development of DM. In contrast, higher expressions of ER, PR and BCL2 were associated with delayed occurrence of DM. DM prediction algorithm was built utilising cases informative for the 15 significant markers. Four risk groups of patients were characterised. Three markers p53, HER2 and BCL2 predicted the probability of DM, based on software-generated cut-offs, with a precision rate of 81.1 % for positive predictive value and 77.3 %, for the negative predictive value. This algorithm reiterates the reported prognostic values of these three markers and underscores their central biological role in BC progression. Further independent validation of this pruned panel of biomarkers is therefore warranted.

Checkpoint kinase1 (CHK1) is an important biomarker in breast cancer having a role in chemotherapy response.

BACKGROUND: Checkpoint kinase1 (CHK1), which is a key component of DNA-damage-activated checkpoint signalling response, may have a role in breast cancer (BC) pathogenesis and influence response to chemotherapy. This study investigated the clinicopathological significance of phosphorylated CHK1 (pCHK1) protein in BC. METHOD: pCHK1 protein expression was assessed using immunohistochemistry in a large, well-characterized annotated series of early-stage primary operable invasive BC prepared as tissue microarray (n=1200). RESULT: pCHK1 showed nuclear and/or cytoplasmic expression. Tumours with nuclear expression showed positive associations with favourable prognostic features such as lower grade, lower mitotic activity, expression of hormone receptor and lack of expression of KI67 and PI3K (P<0.001). On the other hand, cytoplasmic expression was associated with features of poor prognosis such as higher grade, triple-negative phenotype and expression of KI67, p53, AKT and PI3K. pCHK1 expression showed an association with DNA damage response (ATM, RAD51, BRCA1, KU70/KU80, DNA-PKCα and BARD1) and sumoylation (UBC9 and PIASγ) biomarkers. Subcellular localisation of pCHK1 was associated with the expression of the nuclear transport protein KPNA2. Positive nuclear expression predicted better survival outcome in patients who did not receive chemotherapy in the whole series and in ER-positive tumours. In ER-negative and triple-negative subgroups, nuclear pCHK1 predicted shorter survival in patients who received cyclophosphamide, methotrexate and 5-florouracil chemotherapy. CONCLUSIONS: Our data suggest that pCHK1 may have prognostic and predictive significance in BC. Subcellular localisation of pCHK1 protein is related to its function.

KSR1 regulates BRCA1 degradation and inhibits breast cancer growth.

Kinase suppressor of Ras-1 (KSR1) facilitates signal transduction in Ras-dependent cancers, including pancreatic and lung carcinomas but its role in breast cancer has not been well studied. Here, we demonstrate for the first time it functions as a tumor suppressor in breast cancer in contrast to data in other tumors. Breast cancer patients (n>1000) with high KSR1 showed better disease-free and overall survival, results also supported by Oncomine analyses, microarray data (n=2878) and genomic data from paired tumor and cell-free DNA samples revealing loss of heterozygosity. KSR1 expression is associated with high breast cancer 1, early onset (BRCA1), high BRCA1-associated ring domain 1 (BARD1) and checkpoint kinase 1 (Chk1) levels. Phospho-profiling of major components of the canonical Ras-RAF-mitogen-activated protein kinases pathway showed no significant changes after KSR1 overexpression or silencing. Moreover, KSR1 stably transfected cells formed fewer and smaller size colonies compared to the parental ones, while in vivo mouse model also demonstrated that the growth of xenograft tumors overexpressing KSR1 was inhibited. The tumor suppressive action of KSR1 is BRCA1 dependent shown by 3D-matrigel and soft agar assays. KSR1 stabilizes BRCA1 protein levels by reducing BRCA1 ubiquitination through increasing BARD1 abundance. These data link these proteins in a continuum with clinical relevance and position KSR1 in the major oncoprotein pathways in breast tumorigenesis.