Stromal heterogeneity of tumor microenvironment (TME) plays a crucial role in malignancy and therapeutic resistance. Cancer-associated fibroblasts (CAFs) are one of the major players in tumor stroma. The heterogeneous sources of origin and subsequent impacts of crosstalk with breast cancer cells flaunt serious challenges before current therapies to cure triple-negative breast cancer (TNBC) and other cancers. The positive and reciprocal feedback of CAFs to induce cancer cells dictates their mutual synergy in establishing malignancy. Their substantial role in creating a tumor-promoting niche has reduced the efficacy of several anti-cancer treatments, including radiation, chemotherapy, immunotherapy, and endocrine therapy. Over the years, there has been an emphasis on understanding CAF-induced therapeutic resistance in order to enhance cancer therapy results. CAFs, in the majority of cases, employ crosstalk, stromal management, and other strategies to generate resilience in surrounding tumor cells. This emphasizes the significance of developing novel strategies that target particular tumor-promoting CAF subpopulations, which will improve treatment sensitivity and impede tumor growth. In this review, we discuss the current understanding of the origin and heterogeneity of CAFs, their role in tumor progression, and altering the tumor response to therapeutic agents in breast cancer. In addition, we also discuss the potential and possible approaches for CAF-mediated therapies.

Fluorine (F-) is a chemically reactive electronegative univalent gaseous halogen found in small amount in the water, air, plants and animals. Fluorine is essential for the maintenance and solidification of our bones and to prevent dental decay. It has beneficial effects on teeth and bones when it is present at low concentration in drinking water, but excessive exposure to fluoride in drinking-water, or in combination with exposure to fluoride from other sources, can give rise to a number of adverse effects which include teeth decay, osteoporosis and harm to kidney, bones, reproductive organs, nerve and muscle. Fluoride, when in excess, is known to interfere with thyroid gland function causing TSH elevation and lessen T3/T4 hormones in some populations which may be due to its antagonistic properties towards iodine. As an endocrine disruptor, F- induces more toxic outcome in diabetic patients. Chronic F- exposure through drinking water may leads to insulin resistance in humans in addition to its hyperglycemic effect due to increased hepatic glycogenolysis. Fluoride also hinders glycolysis by inhibiting enolase enzyme and repressed insulin secretion from islets of Langerhans cells resulting in elevation of blood glucose level. High F- exposure is also associated with increased levels of FSH and LH, decreased estrogen and testosterone levels, disturbed androgen to estrogen ratios (A/E) and estrogen receptor to androgen receptor ratios (ER/AR). Decreased circulating testosterone concentrations were also reported in male skeletal fluorosis patients. The most significant consequences of fluoride exposures in male reproduction are: changes in the structure and functional activities of spermatozoa and disruption of spermatogenesis while in an experimental data involving female rats showed that high fluoride concentration lowers the pregnancy rate and the number of implantation. Most interestingly, recent research showed that exposure to high concentration of F- does have deleterious effect on the mental ability of children. A strong association between exposure to fluoride and low IQ was found and it was also noted that children who live in fluorosis prevalent areas have higher chances of developing a low IQ than those who live in normal areas. So it is clear that the severity of the above pathological conditions is dependent on the dose, duration and age of the individual. Therefore, to ensure whether people need any fluoride supplements or not, government should have to take initiative to prevent health problems due to deficiency or excess fluoride exposure. Evidence-wise further thorough research is essential based on scientific facts to enlighten best practices in the use of fluoride containing materials for the safety and security of public health.

Chronic exposure to high glucose inside the human body helps in the progression of cancer by activating various signaling pathways including PI3K, Akt, mTOR, Ras, Raf, MAPK, and PKC. Hyperglycemia induces ROS and AGE production and decreases the functional activities of the cellular antioxidant system. By downregulating the prolyl hydroxylase, it stabilizes HIF-α leading to EMT-induced cancer progression and inhibition of apoptosis. High glucose level increases inflammation by creating a pro-inflammatory environment through the production of certain pro-inflammatory mediators (cytokines, chemokines, leukotrienes), and by influencing the recruitment of immune cells, leukocytes in the inflamed region. High glucose impairs the immune response and dysregulates ROS formation through the alteration in ETC and glutaminolysis which makes hyperglycemic patients more susceptible to viral infection. 2-DG is a modified form of D-glucose, that shows anticancer, anti-inflammatory, and anti-viral effects. It enters the cells through GLUT transporters and is converted into 2-deoxy-D-glucose-6-phosphate with the help of hexokinase. It inhibits the glycolysis, the TCA cycle, and the pentose phosphate pathway leading to ATP depletion. By downregulating glucose uptake and energy (ATP) production it halts various pathways responsible for cancer progression. It promotes the formation of anti-inflammatory mediators, and macrophage polarization, and also modulates immune function, which decreases inflammation. 2-DG inhibits PI3K/Akt/mTOR and upregulates the AMPK pathway, causing activation of the SIRT-4 gene that reduces lipogenesis, glucose uptake, nucleotide formation, and alters viral replication thus reducing the chances of infection.