Co-chaperone BAG2 Determines the Pro-oncogenic Role of Cathepsin B in Triple-Negative Breast Cancer Cells

Triple-negative breast cancer (TNBC) is considered incurable with currently available treatments, highlighting the need for therapeutic targets and predictive biomarkers. Here, we report a unique role for Bcl-2-associated athanogene 2 (BAG2), which is significantly overexpressed in TNBC, in regulating the dual functions of cathepsin B as either a pro- or anti-oncogenic enzyme. Silencing BAG2 suppresses tumorigenesis and lung metastasis and induces apoptosis by increasing the intracellular mature form of cathepsin B, whereas BAG2 expression induces metastasis by blocking the auto-cleavage processing of pro-cathepsin B via interaction with the propeptide region. BAG2 regulates pro-cathepsin B/annexin II complex formation and facilitates the trafficking of pro-cathespin-B-containing TGN38-positive vesicles toward the cell periphery, leading to the secretion of pro-cathepsin B, which induces metastasis. Collectively, our results uncover BAG2 as a regulator of the oncogenic function of pro-cathepsin B and a potential diagnostic and therapeutic target that may reduce the burden of metastatic breast cancer

Knowledge, attitudes, and behaviors toward fertility preservation in patients with breast cancer: A cross-sectional survey of physicians

BackgroundFertility is an important issue for young women with breast cancer, but studies about physicians’ knowledge, attitudes, and practices toward fertility preservation (FP) are largely based on Western populations and do not reflect recent international guidelines for FP. In this international study, we aimed to assess the knowledge, attitudes, and practices of physicians from South Korea, other Asian countries, and Latin America toward FP in young women with breast cancer, and identify the related barriers.MethodsThe survey was conducted anonymously among physicians from South Korea, other Asian countries, and Latin America involved in breast cancer care between November 2020 and July 2021. Topics included knowledge, attitudes, and perceptions toward FP; practice behaviors; barriers; and participant demographics. We grouped related questions around two main themes—discussion with patients about FP, and consultation and referral to a reproductive endocrinologist. We analyzed the relationships between main questions and other survey items.ResultsA total of 151 physicians completed the survey. Most participants’ overall knowledge about FP was good. More than half of the participants answered that they discussed FP with their patients in most cases, but that personnel to facilitate discussions about FP and the provision of educational materials were limited. A major barrier was time constraints in the clinic (52.6%). Discussion, consultations, and referrals were more likely to be performed by surgeons who primarily treated patients with operable breast cancer (FP discussion odds ratio [OR]: 2.90; 95% confidence interval [CI]: 1.24–6.79; FP consultation and referral OR: 2.98; 95% CI: 1.14–7.74). Participants’ knowledge and attitudes about FP were significantly associated with discussion, consultations, and referrals.ConclusionPhysicians from South Korea, other Asian countries, and Latin America are knowledgeable about FP and most perform practice behaviors toward FP well. Physicians’ knowledge and favorable attitudes are significantly related to discussion with patients, as well as consultation with and referral to reproductive endocrinologists. However, there are also barriers, such as limitations to human resources and materials, suggesting a need for a systematic approach to improve FP for young women with breast cancer

Subtypes of breast cancer show different spatial distributions of brain metastases - Fig 3

<p><b>The percentages of BMs were plotted across all patients (A), patients with triple negative gene type (B), patients with HER2+ gene type (C), and patients with Luminal type (D).</b> Brain regions were sorted in the order of the frontal, limbic, occipital, parietal, subcortical (SubCor), temporal, and cerebellum. Brain regions above dotted-line indicate the top 10% frequently occurring BMs. Reddish points indicate brain regions showing significant group differences from χ2 test.</p

Subtypes of breast cancer show different spatial distributions of brain metastases

<div><p>The aim of our study was to test the hypothesis that the spatial distribution of breast cancer brain metastases (BM) differ according to their biological subtypes. MR images of 100 patients with BM from primary breast cancer were retrospectively reviewed. Patients were divided according to the biological subtype of the primary tumor, (triple-negative: 24, HER2 positive: 48, luminal: 28). All images marked with BMs were standardized to the human brain MRI atlas provided by the Montreal Neurological Institute 152 database. Distribution pattern of BM was evaluated with intra-group and intergroup analysis. In intra-group analysis, hot spots of metastases from triple-negative are evenly distributed in the brain, meanwhile BMs from HER2 positive and luminal type occur dominantly in occipital lobe and cerebellum. In intergroup analysis, BMs from triple-negative type occurred more often in frontal lobe, limbic region, and parietal lobe, compared with other types (<i>P</i> < .05). Breast cancer subtypes tend to demonstrate different spatial distributions of their BMs. These findings may have direct implications for dose modulation in prophylactic irradiation as well as for differential diagnoses. Thus, this result should be validated in future study with a larger population.</p></div

Correlation of Yes-Associated Protein 1 with Stroma Type and Tumor Stiffness in Hormone-Receptor Positive Breast Cancer

(1) Background: Yes-associated protein 1 (YAP1) is an oncogene activated under the dysregulated Hippo pathway. YAP1 is also a mechanotransducer that is activated by matrix stiffness. So far, there are no in vivo studies on YAP1 expression related to stiffness. We aimed to investigate the association between YAP1 activation and tumor stiffness in human breast cancer samples, using immunohistochemistry and shear-wave elastography (SWE). (2) Methods: We included 488 patients with treatment-naïve breast cancer. Tumor stiffness was measured and the mean, maximal, and minimal elasticity values and elasticity ratios were recorded. Nuclear YAP1 expression was evaluated by immunohistochemistry and tumor-infiltrating lymphocytes (TILs); tumor-stroma ratio (TSR) and stroma type of tumors were also evaluated. (3) Results: Tumor stiffness was higher in tumors with YAP1 positivity, low TILs, and high TSR and was correlated with nuclear YAP1 expression; this correlation was observed in hormone receptor positive (HR+) tumors, as well as in tumors with non-collagen-type stroma. (4) Conclusions: We confirmed the correlation between nuclear YAP1 expression and tumor stiffness, and nuclear YAP1 expression was deemed a prognostic candidate in HR+ tumors combined with SWE-measured tumor stiffness

Heat maps of brain metastases (BMs).

<p>Overlapping of BMs across all patients with breast cancer (A), patients with triple negative type (B), patients with HER2+ type (C), and patients with Luminal type (D). Color-bars indicate the percentage of BMs. Abbreviations: CBL, cerebellum; IFG, inferior frontal gyrus; MFG, middle frontal gyrus; L, left; R, right; MO, middle occipital; PMC, premotor cortex.</p

Patient characteristics.

<p>Patient characteristics.</p