Adiponectin is one of the most important adipocytokines secreted by adipocytes and is called a “guardian angel adipocytokine” owing to its unique biological functions. Adiponectin inversely correlates with body fat mass and visceral adiposity. Identified independently by four different research groups, adiponectin has multiple names; Acrp30, apM1, GBP28, and AdipoQ. Adiponectin mediates its biological functions via three known receptors, AdipoR1, AdipoR2, and T-cadherin, which are distributed throughout the body. Biological functions of adiponectin are multifold ranging from anti-diabetic, anti-atherogenic, anti-inflammatory to anti-cancer. Lower adiponectin levels have been associated with metabolic syndrome, type 2 diabetes, insulin resistance, cardiovascular diseases, and hypertension. A plethora of experimental evidence supports the role of obesity and increased adiposity in multiple cancers including breast, liver, pancreatic, prostrate, ovarian, and colorectal cancers. Obesity mediates its effect on cancer progression via dysregulation of adipocytokines including increased production of oncogenic adipokine leptin along with decreased production of adiponectin. Multiple studies have shown the protective role of adiponectin in obesity-associated diseases and cancer. Adiponectin modulates multiple signaling pathways to exert its physiological and protective functions. Many studies over the years have shown the beneficial effect of adiponectin in cancer regression and put forth various innovative ways to increase adiponectin levels.

The microbiome is undoubtedly the second genome of the human body and has diverse roles in health and disease. However, translational progress is limited due to the vastness of the microbiome, which accounts for over 3.3 million genes, whose functions are still unclear. Numerous studies in the past decade have demonstrated how microbiome impacts various organ-specific cancers by altering the energy balance of the body, increasing adiposity, synthesizing genotoxins and small signaling molecules, and priming and regulating immune response and metabolism of indigestible dietary components, xenobiotics, and pharmaceuticals. In relation to breast cancer, one of the most prominent roles of the human microbiome is the regulation of steroid hormone metabolism since endogenous estrogens are the most important risk factor in breast cancer development especially in postmenopausal women. Intestinal microbes encode enzymes capable of deconjugating conjugated estrogen metabolites marked for excretion, pushing them back into the enterohepatic circulation in a biologically active form. In addition, the intestinal microbes also break down otherwise indigestible dietary polyphenols to synthesize estrogen-like compounds or estrogen mimics that exhibit varied estrogenic potency. The present account discusses the potential role of gastrointestinal microbiome in breast cancer development by mediating metabolism of steroid hormones and synthesis of biologically active estrogen mimics.

The existence of distinct breast microbiota has been recently established, but their biological impact in breast cancer remains elusive. Focusing on the shift in microbial community composition in diseased breast compared with normal breast, we identified the presence of Bacteroides fragilis in cancerous breast. Mammary gland as well as gut colonization with enterotoxigenic Bacteroides fragilis (ETBF), which secretes B. fragilis toxin (BFT), rapidly induces epithelial hyperplasia in the mammary gland. Breast cancer cells exposed to BFT exhibit “BFT memory” from the initial exposure. Intriguingly, gut or breast duct colonization with ETBF strongly induces growth and metastatic progression of tumor cells implanted in mammary ducts, in contrast to nontoxigenic Bacteroides fragilis. This work sheds light on the oncogenic impact of a procarcinogenic colon bacterium ETBF on breast cancer progression, implicates the β-catenin and Notch1 axis as its functional mediators, and proposes the concept of “BFT memory” that can have far-reaching biological implications after initial exposure to ETBF. Significance: B. fragilis is an inhabitant of breast tissue, and gut or mammary duct colonization with ETBF triggers epithelial hyperplasia and augments breast cancer growth and metastasis. Short-term exposure to BFT elicits a “BFT memory” with long-term implications, functionally mediated by the β-catenin and Notch1 pathways. This article is highlighted in the In This Issue feature, p. 995

Disparate occurrence of breast cancer remains an intriguing question since only a subset of women with known risk factors develop cancer. Recent studies suggest an active role of local and distant microbiota in breast cancer initiation, progression, and overall prognosis. A dysbiotic microbiota predisposes the body to develop cancer by inducing genetic instability, initiating DNA damage and proliferation of the damaged progeny, eliciting favorable immune response, metabolic dysregulation and altered response to therapy. In this review, we present our analyses of the existing datasets and discuss the local dysbiosis observed in breast cancer patients and different aspects of breast carcinogenesis that can be potentially influenced by local breast microbiota. Striking differences between microbial community compositions in breast of cancer patients compared to healthy individuals were noted. Differences in microbiome were also apparent between benign and malignant disease and between nipple aspirate fluid of healthy individuals and breast survivors. We also discuss the identification of distinct bacterial, fungal, viral as well as parasite signatures for breast cancer. These microbes are capable of producing numerous secondary metabolites that can act as signaling mediators effecting breast cancer progression. We review how microbes potentially alter response to therapy affecting drug metabolism, pharmacokinetics, anti-tumor effects and toxicity. In conclusion, breast harbors a community of microbes that can communicate with the host cells inducing downstream signaling pathways and modulating various aspects of breast cancer growth and metastatic progression and an improved understanding of microbial dysbiosis can potentially reduce breast cancer risk and improve outcomes of breast cancer patients. The human microbiome, now referred to as, the “forgotten organ” contains a metagenome that is 100-fold more diverse compared to the human genome, thereby, is critically associated with human health [ 1 , 2 ]. With the revelations of the human microbiome project and advent of deep sequencing techniques, a plethora of information has been acquired in recent years. Body sites like stomach, bladder and lungs, once thought to be sterile, are now known to harbor millions of indigenous microbial species. Approximately 80% of the healthy microbiome consists of Firmicutes and Bacteroidetes accompanied by Verrucomicrobia , Actinobacteria , Proteobacteria , Tenericutes and Cyanobacteria [ 2 – 7 ]. The role of microbiome in diabetes, obesity and even neurodegenerative diseases was greatly appreciated in the last decade [ 1 , 7 – 14 ] and now it has been established that microbiome significantly contr...

Breast cancer-related mortality remains high worldwide, despite tremendous advances in diagnostics and therapeutics; hence, the quest for better strategies for disease management, as well as the identification of modifiable risk factors, continues. With recent leaps in genomic technologies, microbiota have emerged as major players in most cancers, including breast cancer. Interestingly, microbial alterations have been observed with some of the established risk factors of breast cancer, such as obesity, aging and periodontal disease. Higher levels of estrogen, a risk factor for breast cancer that cross-talks with other risk factors such as alcohol intake, obesity, parity, breastfeeding, early menarche and late menopause, are also modulated by microbial dysbiosis. In this review, we discuss the association between known breast cancer risk factors and altered microbiota. An important question related to microbial dysbiosis and cancer is the underlying mechanisms by which alterations in microbiota can support cancer progression. To this end, we review the involvement of microbial metabolites as effector molecules, the modulation of the metabolism of xenobiotics, the induction of systemic immune modulation, and altered responses to therapy owing to microbial dysbiosis. Given the association of breast cancer risk factors with microbial dysbiosis and the multitude of mechanisms altered by dysbiotic microbiota, an impaired microbiome is, in itself, an important risk factor.

No abstract

Success of chemotherapy as a treatment for cancer has been often inhibited by multidrug resistance (MDR) of the cancer cells. There is a clear need to generate strategies to overcome this resistance. In this work, we have developed redox-responsive and core-cross-linked micellar nanocarriers using poly(ethylene glycol)-block-poly(2-(methacryloyloxy)ethyl 5-(1,2-dithiolan-3-yl)pentanoate) diblock copolymers (PEG-b-PLAHEMA) with tunable swelling properties for the delivery of drugs toward drug-sensitive MDA-MB-231 and drug-resistant MDA-MB-231 (231R) cancer cells. PEG-b-PLAHEMA containing varying number of 2-(methacryloyloxy)ethyl 5-(1,2-dithiolan-3-yl)pentanoate (LAHEMA) units were synthesized by employing the reversible addition-fragmentation chain transfer polymerization technique. The block copolymer self-assembly, cross-linking induced by reduction, and de-cross-linking triggered time-dependent controlled swelling of micelles were studied using dynamic light scattering, fluorescence spectroscopy, and transmission electron microscopy. In vitro cytotoxicity, cellular uptake efficiency, and glutathione-responsive anticancer activity of doxorubicin (DOX) encapsulated in core-cross-linked block copolymer micelles (CCMs) toward both drug-sensitive and drug-resistant cancer cell lines were evaluated. Significant reduction in IC was observed by DOX-loaded CCMs toward drug-resistant 231R cancer cell lines, which was further improved by coencapsulating DOX and verapamil (a P-glycoprotein inhibitor) in CCMs. Thus, these reduction-sensitive biocompatible CCMs with tunable swelling property are very promising in overcoming MDR in cancer cells.

No abstract