Despite a remarkable increase in the depth of our understanding and management of breast cancer in the past 50 years, the disease is still a major public health problem worldwide and poses significant challenges. The palpability of breast tumors has facilitated diagnosis and documentation since ancient times. The earliest descriptions of breast cancer date back to around 3500 BCE. For centuries to follow, theories by Hippocrates (460 BCE) and Galen (200 CE), attributing the cause of breast cancer to an "excess of black bile" and treatment options including the use of opium and castor oil, prevailed. Surgical resection was introduced in the 18th century. The advent of modern medicine led to the development of novel treatment options that include hormonal, targeted and chemo-therapies. There are still several therapeutic challenges including the treatment of triple negative breast cancer (TNBC), and overcoming drug resistance. The increased incidence and awareness of breast cancer has led to significant changes in diagnosis and treatment in recent decades. But, mankind has come a long way. Herein, I have traced how our understanding of breast cancer has evolved from the early description of the disease around 460 BCE as "black bile-containing crab-like tumors" to the conventional as a heterogeneous disease with high degree of diversity between and within tumors, as well as among breast cancer patients. How is breast cancer treated today and how do risk factors, breast cancer subtype and drug resistance contribute to the therapeutic challenges at the turn of the 21st century? Breast cancer remains a serious public health issue worldwide. However, appreciable growth in our understanding of breast cancer in the past century has led to remarkable progress in the early detection, treatment and prevention of the disease. The clinical focus is shifting more towards tailored therapy as more targets are characterized and novel highly innovative approaches are developed. Tracing the history of breast cancer, highlights how increased awareness of the disease, and progress in research and development have enhance our understanding of the disease.

Breast cancer is the most frequent type of malignancy in women worldwide, and drug resistance to the available systemic therapies remains a major challenge. At the molecular level, breast cancer is heterogeneous, where the cancer-initiating stem-like cells (bCSCs) comprise a small yet distinct population of cells within the tumor microenvironment (TME) that can differentiate into cells of multiple lineages, displaying varying degrees of cellular differentiation, enhanced metastatic potential, invasiveness, and resistance to radio- and chemotherapy. Based on the expression of estrogen and progesterone hormone receptors, expression of human epidermal growth factor receptor 2 (HER2), and/or BRCA mutations, the breast cancer molecular subtypes are identified as TNBC, HER2 enriched, luminal A, and luminal B. Management of breast cancer primarily involves resection of the tumor, followed by radiotherapy, and systemic therapies including endocrine therapies for hormone-responsive breast cancers; HER2-targeted therapy for HER2-enriched breast cancers; chemotherapy and poly (ADP-ribose) polymerase inhibitors for TNBC, and the recent development of immunotherapy. However, the complex crosstalk between the malignant cells and stromal cells in the breast TME, rewiring of the many different signaling networks, and bCSC-mediated processes, all contribute to overall drug resistance in breast cancer. However, strategically targeting bCSCs to reverse chemoresistance and increase drug sensitivity is an underexplored stream in breast cancer research. The recent identification of dysregulated miRNAs/ncRNAs/mRNAs signatures in bCSCs and their crosstalk with many cellular signaling pathways has uncovered promising molecular leads to be used as potential therapeutic targets in drug-resistant situations. Moreover, therapies that can induce alternate forms of regulated cell death including ferroptosis, pyroptosis, and immunotherapy; drugs targeting bCSC metabolism; and nanoparticle therapy are the upcoming approaches to target the bCSCs overcome drug resistance. Thus, individualizing treatment strategies will eliminate the minimal residual disease, resulting in better pathological and complete response in drug-resistant scenarios. This review summarizes basic understanding of breast cancer subtypes, concept of bCSCs, molecular basis of drug resistance, dysregulated miRNAs/ncRNAs patterns in bCSCs, and future perspective of developing anticancer therapeutics to address breast cancer drug resistance.

Purpose: Breast cancer, the most prevalent cancer worldwide, consists of 4 main subtypes, namely, Luminal A, Luminal B, HER2-positive, and Triple-negative breast cancer (TNBC). Triple-negative breast tumors, which do not express estrogen, progesterone, and HER2 receptors, account for approximately 15-20% of breast cancer cases. The lack of traditional receptor targets contributes to the heterogenous, aggressive, and refractory nature of these tumors, resulting in limited therapeutic strategies. Methods: Chemotherapeutics such as taxanes and anthracyclines have been the traditional go to treatment regimens for TNBC patients. Paclitaxel, docetaxel, doxorubicin, and epirubicin have been longstanding, Food and Drug Administration (FDA)-approved therapies against TNBC. Additionally, the FDA approved PARP inhibitors such as olaparib and atezolizumab to be used in combination with chemotherapies, primarily to improve their efficiency and reduce adverse patient outcomes. The immunotherapeutic Keytruda was the latest addition to the FDA-approved list of drugs used to treat TNBC. Results: The following review aims to elucidate current FDA-approved therapeutics and their mechanisms of action, shedding a light on the various strategies currently used to circumvent the treatment-resistant nature of TNBC cases. Conclusion: The recent approval and use of therapies such as Trodelvy, olaparib and Keytruda has its roots in the development of an understanding of signaling pathways that drive tumour growth. In the future, the emergence of novel drug delivery methods may help increase the efficiency of these therapies whiel also reducing adverse side effects.

Breast cancer is one of the most significant causes of mortality among women and the second most prevalent cancer worldwide. Estrogen receptor (ER)-positive breast cancers are the most common molecular subtype of breast cancer, comprising about 70% of breast carcinoma diagnoses worldwide. Endocrine therapy is the foremost strategy for the treatment of ER-positive breast cancer. In the United States, the Food and Drug Administration (FDA) has approved endocrine therapies for ER-positive breast cancers that include selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators/degraders (SERDs) and aromatase inhibitors (AIs). The approved SERMS, tamoxifen, toremifene and raloxifene, are the gold-standard treatments. The only FDA-approved SERD available for treating ER and hormone-positive breast cancers is fulvestrant, and various generations of AIs, including exemestane, letrozole, and anastrozole, have also received FDA approval. Herein, we review the major FDA-approved SERMs and SERDs for treating ER-positive breast cancer, focusing on their mechanisms of action. We also explore molecular events that contribute to the resistance of these drugs to endocrine therapies and combinational strategies with drugs such as cyclin-dependant kinases 4/6 (CDK4/6) inhibitors in clinical trials to combat endocrine drug resistance.