The complex signaling network within the breast tumor microenvironment is crucial for its growth, metastasis, angiogenesis, therapy escape, stem cell maintenance, and immunomodulation. An array of secretory factors and their receptors activate downstream signaling cascades regulating breast cancer progression and metastasis. Among various signaling pathways, the EGFR, ER, Notch, and Hedgehog signaling pathways have recently been identified as crucial in terms of breast cancer proliferation, survival, differentiation, maintenance of CSCs, and therapy failure. These receptors mediate various downstream signaling pathways such as MAPK, including MEK/ERK signaling pathways that promote common pro-oncogenic signaling, whereas dysregulation of PI3K/Akt, Wnt/β-catenin, and JAK/STAT activates key oncogenic events such as drug resistance, CSC enrichment, and metabolic reprogramming. Additionally, these cascades orchestrate an intricate interplay between stromal cells, immune cells, and tumor cells. Metabolic reprogramming and adaptations contribute to aggressive breast cancer and are unresponsive to therapy. Herein, recent insights into the novel signaling pathways operating within the breast TME that aid in their advancement are emphasized and current developments in practices targeting the breast TME to enhance treatment efficacy are reviewed.

Curcumin is a nutraceutical known to have numerous medicinal effects including anticancer activity. However, due to its poor water solubility and bioavailability, the therapeutic impact of curcumin against cancer, including breast cancer, has been constrained. Encapsulating curcumin into chitosan nanoparticles (CHNPs) is an effective method to increase its bioavailability as well as antitumorigenic activity. In the current study, the effects of curcumin-encapsulated CHNPs (Cur-CHNPs) on cell migration, targeted homing and tumor growth were examined using in vitro and in vivo breast cancer models. Cur-CHNPs possessed a monodispersed nature with long-term colloidal stability, and demonstrated significant inhibition of cell viability in vitro, which was potentiated by 5-Fluorouracil (5-FU). Outcomes of the in vivo imaging studies confirmed effective tumor targeting and retention ability of Cur-CHNPs, thereby suppressing breast tumor growth in mice models. Overall, the results demonstrated that Cur-CHNPs could be an effective candidate drug formulation for management of breast cancer.

The tumor microenvironment (TME) is composed of various cellular components such as tumor cells, stromal cells including fibroblasts, adipocytes, mast cells, lymphatic vascular cells and infiltrating immune cells, macrophages, dendritic cells and lymphocytes. The intricate interplay between these cells influences tumor growth, metastasis and therapy failure. Significant advancements in breast cancer therapy have resulted in a substantial decrease in mortality. However, existing cancer treatments frequently result in toxicity and nonspecific side effects. Therefore, improving targeted drug delivery and increasing the efficacy of drugs is crucial for enhancing treatment outcome and reducing the burden of toxicity. In this review, we have provided an overview of how tumor and stroma-derived osteopontin (OPN) plays a key role in regulating the oncogenic potential of various cancers including breast. Next, we dissected the signaling network by which OPN regulates tumor progression through interaction with selective integrins and CD44 receptors. This review addresses the latest advancements in the roles of splice variants of OPN in cancer progression and OPN-mediated tumor-stromal interaction, EMT, CSC enhancement, immunomodulation, metastasis, chemoresistance and metabolic reprogramming, and further suggests that OPN might be a potential therapeutic target and prognostic biomarker for the evolving landscape of cancer management.

Cancer is one of the leading public health issues with poor prognosis, high mortality rate, and limited effective treatment strategies. Hypoxia, a common characteristic feature of solid tumors, is caused by structural and functional modifications in microvasculature. Hypoxia-inducible factor-1 (HIF-1) is the principal regulator of physiological adaptations to hypoxia that activates the expression of battery of target genes, leading to the development of cancer, stromal angiogenesis, metastasis, and drug resistance by targeting MMPs, VEGF, LOX, and STAT3. It also stimulates complex cancer signaling networks, including PI3K and MAPK pathways. We have discussed how hypoxia regulates progression of various cancers, including breast, ovarian, cervical, and prostate, and their metastasis, angiogenesis, and drug resistance for better understanding of the implications of hypoxia in cancer therapy.

Over the last two decades, therapeutic nanoparticles have emerged as potential candidates for improving cancer chemotherapy, including for breast cancer. Various kinds of nanoplatforms have been developed for this purpose, including stimuli-responsive nanocarriers. Stimuli-responsive nanocarriers can provide effective and controlled drug delivery in response to a physicochemical stimulus such as pH. It has been well established that solid tumors possess an acidic tumor microenvironment, which can be exploited for targeting and controlling the release of drugs by pH-sensitive nanocarriers. In this chapter, the authors discuss various pH-responsive nanosystems for breast cancer therapy. Various mechanisms and strategies that have been used to design pH-responsive nanomaterials are described. Further, different pH-sensitive nanoparticle systems that are utilized in the treatment of breast cancer are reviewed in depth.