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Introduction Breast cancer cells display preferences for specific metastatic sites including the bone, lung and liver. Metastasis is a complex process that relies, in part, on interactions between disseminated cancer cells and resident/infiltrating stromal cells that constitute the metastatic microenvironment. Distinct immune infiltrates can either impair the metastatic process or conversely, assist in the seeding, colonization and growth of disseminated cancer cells. Methods Using in vivo selection approaches, we previously isolated 4T1-derived breast cancer cells that preferentially metastasize to these organs and tissues. In this study, we examined whether the propensity of breast cancer cells to metastasize to the lung, liver or bone is associated with and dependent on distinct patterns of immune cell infiltration. Immunohistocytochemistry and immunohistofluorescence approaches were used to quantify innate immune cell infiltrates within distinct metastases and depletion of Gr1 + (Ly-6C and Ly-6G) or specifically Ly-6G + cells was performed to functionally interrogate the role of Ly-6G + infiltrates in promoting metastasis to these organs. Results We show that T lymphocytes (CD3 + ), myeloid-derived (Gr-1 + ) cells and neutrophils (Ly-6G + or NE + ) exhibit the most pronounced recruitment in lung and liver metastases, with markedly less recruitment within bone metastatic lesions. Interestingly, these infiltrating cell populations display different patterns of localization within soft tissue metastases. T lymphocytes and granulocytic immune infiltrates are localized around the periphery of liver metastases whereas they were dispersed throughout the lung metastases. Furthermore, Gr-1 + cell-depletion studies demonstrate that infiltrating myeloid-derived cells are essential for the formation of breast cancer liver metastases but dispensable for metastasis to the lung and bone. A specific role for the granulocytic component of the innate immune infiltrate was revealed through Ly-6G + cell-depletion experiments, which resulted in significantly impaired formation of liver metastases. Finally, we demonstrate that the CD11b + /Ly-6G + neutrophils that infiltrate and surround the liver metastases are polarized toward an N2 phenotype, which have previously been shown to enhance tumor growth and metastasis. Conclusions Our results demonstrate that the liver-metastatic potential of breast cancer cells is heavily reliant on interactions with infiltrating Ly-6G + cells within the liver microenvironment.

Molecularly targeted therapies are rapidly growing with respect to their clinical development and impact on cancer treatment due to their highly selective anti-tumor action. However, many aggressive cancers such as triple-negative breast cancer (TNBC) currently lack well-defined therapeutic targets against which such agents can be developed. The identification of tumor-associated antigens and the generation of antibody drug-conjugates represent an emerging area of intense interest and growth in the field of cancer therapeutics. Glycoprotein non-metastatic b (GPNMB) has recently been identified as a gene that is over-expressed in numerous cancers, including TNBC, and often correlates with the metastatic phenotype. In breast cancer, GPNMB expression in the tumor epithelium is associated with a reduction in disease-free and overall survival. Based on these findings, glembatumumab vedotin (CDX-011), an antibody-drug conjugate that selectively targets GPNMB, is currently being investigated in clinical trials for patients with metastatic breast cancer and unresectable melanoma. This review discusses the physiological and potential pathological roles of GPNMB in normal and cancer tissues, respectively, and details the clinical advances and challenges in targeting GPNMB-expressing malignancies.

In the past decade, our understanding of the molecular mechanisms that underlie breast cancer pathology and progression has dramatically improved. Using this knowledge, we have identified additional targets and developed novel therapeutic interventions in breast cancer. Together, these translational research efforts are helping to usher us into an age of personalized cancer therapy. Metastasis to bone is a common and devastating consequence of breast cancer. Bisphosphonates, which represent the current gold standard in bone metastasis therapies, are being improved with newer and more efficacious generations of these compounds being developed. Breast cancer growth in the bone requires activation of various signaling pathways in both cancer cells and stromal cells, including those that are stimulated by TGF- β and RANKL, and mediated through the Src tyrosine kinase. Bone cells and cancer cells alike express promising targets for therapeutic intervention, including Cathepsin K, CXCR4 and GPNMB. In this article we discuss the molecular mechanisms behind these pro-metastatic molecules and review the most recent findings in the clinical development of their associated targeted therapies.

Glycoprotein non-metastatic melanoma protein B (GPNMB)/Osteoactivin (OA) is a transmembrane protein expressed in approximately 40-75% of breast cancers. GPNMB/OA promotes the migration, invasion and metastasis of breast cancer cells; it is commonly expressed in basal/triple-negative breast tumors and is associated with shorter recurrence-free and overall survival times in patients with breast cancer. Thus, GPNMB/OA represents an attractive target for therapeutic intervention in breast cancer; however, little is known about the functions of GPNMB/OA within the primary tumor microenvironment. We have employed mouse and human breast cancer cells to investigate the effects of GPNMB/OA on tumor growth and angiogenesis. GPNMB/OA-expressing tumors display elevated endothelial recruitment and reduced apoptosis when compared to vector control-derived tumors. Primary human breast cancers characterized by high vascular density also display elevated levels of GPNMB/OA when compared to those with low vascular density. Using immunoblot and ELISA assays, we demonstrate the GPNMB/OA ectodomain is shed from the surface of breast cancer cells. Transient siRNA-mediated knockdown studies of known sheddases identified ADAM10 as the protease responsible for GPNMB/OA processing. Finally, we demonstrate that the shed extracellular domain (ECD) of GPNMB/OA can promote endothelial migration in vitro. GPNMB/OA expression promotes tumor growth, which is associated with enhanced endothelial recruitment. We identify ADAM10 as a sheddase capable of releasing the GPNMB/OA ectodomain from the surface of breast cancer cells, which induces endothelial cell migration. Thus, ectodomain shedding may serve as a novel mechanism by which GPNMB/OA promotes angiogenesis in breast cancer.

Women have traditionally been underrepresented in MD and MD-PhD training programs. Here, we describe the changing demographics of an MD-PhD Program over three distinct time intervals. We designed a 64-question survey and sent it to 47 graduates of the McGill University MD-PhD program in Montréal, Québec, Canada, since its inception in 1985. We also sent a 23-question survey to the 24 students of the program in 2021. The surveys included questions related to demographics, physician-scientist training, research metrics, as well as academic and personal considerations. We collected responses from August 2020 to August 2021 and grouped them into three intervals based on respondent graduation year: 1995-2005 (n = 17), 2006-2020 (n = 23) and current students (n = 24). Total response rate was 90.1% (n = 64/71). We found that there are more women currently in the program compared to the 1995-2005 cohort (41.7% increase, p<0.01). In addition, women self-reported as physician-scientists less frequently than men and reported less protected research time. Overall, recent MD-PhD alumni represent a more diverse population compared with their earlier counterparts. Identifying barriers to training remains an important step in ensuring MD-PhD trainees become successful physician-scientists.

The RAS–RAF–MEK–ERK signaling cascade is among the most frequently mutated pathways in human cancer. Approximately 50% of melanoma patients possess a druggable hotspot V600E/K mutation in the BRAF protein kinase. FDA-approved combination therapies of BRAF and MEK inhibitors are available that provide survival benefits to patients with a BRAF V600 mutation. Non-V600 BRAF mutants are found in many cancers, and are more prevalent than V600 mutations in certain tumor types. For example, between 50–80% of BRAF mutations in non-small cell lung cancer and 22–30% in colorectal cancer encode for non-V600 mutants. As next generation sequencing becomes increasingly used in clinical practice, oncologists are frequently identifying non-V600 BRAF mutations in their patient’s tumors, but are uncertain of viable therapeutic options that could be employed for optimal treatment. From recent studies, a new classification system is emerging for BRAF mutations based on biochemical and signaling mechanisms associated with these mutants. Class I BRAF mutations affect amino acid V600 and signal as RAS-independent active monomers, class II mutations function as RAS-independent activated dimers, and class III mutations are kinase impaired but increase signaling through the MAPK pathway due to enhanced RAS binding and subsequent CRAF activation. These distinct classes of BRAF mutations predict response to targeted therapies and have important implications for future drug development. Herein, we discuss pre-clinical and clinical findings that may lead to improved treatments for all classes of BRAF mutant cancers.

The RAF family of kinases includes key activators of the pro-tumourigenic mitogen-activated protein kinase pathway. Hyperactivation of RAF proteins, particularly BRAF and CRAF, drives tumour progression and drug resistance in many types of cancer. Although BRAF is the most studied RAF protein, partially owing to its high mutation incidence in melanoma, the role of CRAF in tumourigenesis and drug resistance is becoming increasingly clinically relevant. Here, we summarize the main known regulatory mechanisms and gene alterations that contribute to CRAF activity, highlighting the different oncogenic roles of CRAF, and categorize RAF1 (CRAF) mutations according to the effect on kinase activity. Additionally, we emphasize the effect that CRAF alterations may have on drug resistance and how precision therapies could effectively target CRAF-dependent tumours. Here, we discuss preclinical and clinical findings that may lead to improved treatments for all types of oncogenic RAF1 alterations in cancer. Although hyperactivation of BRAF has been well-established to drive tumour progression and drug resistance, the role of CRAF in cancer is becoming increasingly relevant. Here, Riaud et al. summarize the various oncogenic roles of CRAF and the potential for CRAF-targeted therapies to improve the clinical outcome for RAF1 altered tumours.

Vitamin D regulates expression of genes important in development and progression of breast cancer. The association of vitamin D with breast cancer outcomes among breast cancer patients is controversial. We conducted a systematic review and meta-analysis of this association in early stage breast cancer outcome. We searched MEDLINE (1982–May 1, 2013), the American Society of Clinical Oncology (2009–2012), and the San Antonio Breast Cancer Symposium (2010–2012) for abstracts, using the following keywords: “breast cancer” and “prognosis” or “survival”, and “vitamin D” or” calcitriol” to identify studies reporting the associations of blood vitamin D levels (drawn close to diagnosis) with breast cancer outcomes. Meta-analyses were performed using an inverse-variance weighted fixed-effects model with Stata Version 12. Eight studies including 5,691 patients were identified. Vitamin D deficiency was variably categorized across studies; a median of 36.8 % of patients were classified as deficient. Low vitamin D levels were associated with a pooled hazard ratio of 2.13 (95 % CI 1.64–2.78) and 1.76 (95 % CIs 1.35–2.30) for recurrence (six studies) and death (four studies), respectively, with no evidence of significant heterogeneity across studies. There was potential evidence of a publication bias in studies examining associations with death (but not in those examining associations with recurrence). These findings support an association of low levels of vitamin D with increased risk of recurrence and death in early stage breast cancer patients. Given the observational nature of the included studies, it cannot be concluded that this association is causal. Further research is warranted to investigate the potential beneficial effects of vitamin D in breast cancer.

Contributor Roles Taxonomy (CRediT) has recently changed how author contributions are acknowledged. To extend and complement CRediT, we propose MeRIT, a new way of writing the Methods section using the author’s initials to further clarify contributor roles for reproducibility and replicability.