Prostate cancer (PCa) and breast cancer (BCa) are two common types of malignant tumor with high mortality rates. According to recent statistical data, the number of new cases of PCa and BCa accounts for 7.1 and 11.6% of the total cancer cases worldwide, and the numbers of deaths from PCa and BCa account for 3.8 and 6.6% of all cancer deaths, respectively (1). Particularly in Asian countries like China, the incidences of PCa and BCa have been constantly increasing over the last two decades (2). Owing to the improved early diagnosis and advanced therapeutic strategies, the mortality rates of PCa and BCa have appreciably decreased. Unfortunately, the majority of patients eventually develop more aggressive malignant forms that are resistant to the most common treatments, leading to a poor prognosis (3,4). Thus, therapeutic resistance still poses a major challenge on the path to conquer PCa and BCa.

As sex hormone-related cancer types, PCa and BCa share a common feature; namely, that the interaction between sex hormones and hormone receptors is required to initiate tumorigenesis (5,6). In PCa, the androgen response is thought to be essential for tumorigenesis. Blockage of the interaction between androgen and the androgen receptor (AR) has been implicated in the induction of caspase-mediated apoptosis, as well as the inhibition of cell proliferation by altering cell cycling (7,8). Like androgen, estrogen is also essential for cell survival and proliferation, and estrogen receptor (ER) activation is recognized to play a pivotal role in BCa progression (9-11). Overall, heightened AR and ER activities are thought to contribute to the development of PCa and BCa through AR/ER-mediated signal transduction.

Since sex hormone responses are a key factor for the initiation of tumorigenesis in both PCa and BCa, hormone deprivation has become a common therapeutic option for the treatment of these two types of cancer. However, although most patients can gain certain therapeutic benefits from hormone therapies in the early stages, a large number of patients eventually acquire therapeutic resistance, leading to tumor recurrence and metastasis in hormone-free conditions (3,12). Overall, the therapeutic strategies for PCa and BCa are quite similar (Table I).

For patients with low- and intermediate-risk localized PCa, local treatment such as prostatectomy and radiotherapy are efficient to prevent distant organ metastasis (13-15). Additionally, radiotherapy plus hormone therapy has been applied to treat patients with high-risk locally advanced PCa, metastatic PCa that is unsuitable for surgery, or tumor recurrence after prostatectomy (13,15,16). Finally, chemotherapy with serious side-effects is still required to treat malignant PCa when hormone therapy is no longer effective (13,15). Notably, recent advanced targeted therapy and immunotherapy for inhibiting malignancy-associated molecules, as well as specific signaling pathways, have been successfully used to control hormone-refractory states (17,18). In BCa treatment, for patients with the early stages of BCa, after breast-conserving surgery or mastectomy, radiotherapy is essential to reduce the risk of recurrence (19,20). Generally, endocrino-therapy is the first-line treatment for ER-positive BCa (21). Ultimately, chemotherapy is essential in treating patients with metastatic BCa, including human epidermal growth factor receptor 2 (HER2)-positive BCa, high-risk luminal HER2-negative BCa and triple-negative BCa (TNBC) (22-24). Likewise, targeted therapy for inhibiting HER2 appears to efficiently treat malignant BCa (25). Immunotherapy also has also become a potent therapeutic approach to controlling BCa progression and reversing drug resistance (26).

Overall, hormone therapy is a powerful tool for the treatment of the early stages of AR-positive PCa or ER-positive BCa. Nevertheless, chemotherapy is necessary for treating late-stage disease that is resistant to hormone therapy. Unfortunately, advanced disease with a metastatic phenotype remains incurable, particularly life-threatening metastases to the bones or brain (27-30). Thus, more efficient targeted therapy and immunotherapy are needed to more effectively treat advanced PCa/BCa. To that end, the aim of the present review was to integrate research on the mechanism by which PCa or BCa gradually progresses to the AR/ER-negative genotype. Activation of the NF-κB pathway appears to play a central role in the progression of hormone-independent malignancies and in endocrinotherapy resistance; in particular, RelB is a key factor in sustaining NF-κB activity to replace the function of AR/ER.

The interaction between ligands and receptors is thought to be essential for normal physiological development, but also to be involved in cancer progression. Abnormal activation of AR/ER signaling uniquely contributes toward the tumorigenesis of PCa/BCa. Nevertheless, unlike PCa with AR alone, the progesterone receptor (PR) and HER2 are also important receptors, along with ER, in BCa.

The functional consequences of cell signaling modulation are mainly ascribed to gene transcriptional regulation in PCa and BCa progression (48,49). AR/ER-mediated transcriptional regulation is thought to be critical for the development of the early stages of PCa/BCa. Nevertheless, AR/ER function eventually declines in the late stages of malignant PCa/BCa, particularly as a consequences of hormone deprivation therapy (50,51). Notably, other transcription factors like NF-κB functionally take over AR/ER to substantially reprogram the cell transcriptome, sustaining PCa/BCa progression under hormone-free conditions (52-54).

Although most patients with PCa and BCa are responsive to endocrinotherapy initially, treatment resistance and tumor relapse remains a salient question in clinical supervision. Indeed, clinical outcomes indicate that hormone deprivation treatment somehow promotes the development of hormone-independent malignant tumor types (83,84). Accordingly, multiple mechanisms have been reported to be relevant to endocrinotherapy resistance, including activation of the NF-κB pathway (47,83-87). Notably, the TNF-a, WNT5A, PI3K-AKT, Ras-Raf-ERK and transforming growth factor (TGF)-β1-mitogen activated protein kinase (MAPK) signaling axes have been demonstrated to be important upstream signaling pathways of the NF-κB pathway in both PCa and BCa (47,85,86,88-92).

As a typical redox responsible transcription factor, NF-κB responds to stimulation with reactive oxygen species (ROS). In the regard, NADPH oxidase 4 leads to ROS production accompanied by mitochondrial respiration, thereby stimulating the NF-κB pathway (88). Anticancer drugs such as TNF-α and adriamycin adapt to increase ROS, in turn induce antioxidant enzymes like manganese superoxide dismutase (MnSOD) through NF-κB activation (88,89). The PI3K-AKT and Ras-Raf-ERK signaling axes have been shown to play pivotal roles in PCa/BCa progression by modulating NF-κB in substitution for AR/ER (47,85,86,90-95). In particular, the activation of the PI3K-AKT-NF-κB signaling axis has been well documented for the development of a hormone-independent phenotype as well as therapeutic resistance in both PCa and BCa (63,96,97). Notably, PI3K activation in PTEN-deficient PCa is a hallmark of an androgen-independent phenotype (17). The results of a previous study suggested a reciprocal feedback between the two oncogenic pathways (98). PI3K activation leads to repression of AR transcriptional output and, consistently, PI3K inhibition activates AR signaling. Conversely, AR inhibition promotes PI3K activity in PTEN-deficient PCa. Thus, combined AR and PI3K inhibition produces improved therapeutic responses (98). Since PI3K is a key upstream signaling molecule for activation of the NF-κB pathway, this finding mechanistically elucidated the inverse association between AR and the NF-κB pathway.

In addition, TGF-β1-induced p38-MAPK signaling upregulates IL-6 expression due to RelA activation (99-101). RalBP1-associated Eps domain-containing protein 2 mediates RelA activation, and was also shown to promote androgen-independent growth (102). Nevertheless, NF-κB has also been shown to cooperate with AR under androgen deprivation conditions; for instance, macrophage stimulating 1 receptor, a receptor tyrosine kinase, is able to activate NF-κB, which is sufficient to drive AR nuclear localization under androgen deprivation condition and support CRPC growth (103).

Notably, the canonical NF-κB pathway can actually induce the noncanonical NF-κB pathway, thereby sustaining high NF-κB activity (76,104). Additionally, several inducible agents have been demonstrated to directly activate the noncanonical NF-κB pathway. WNT5A from bone stromal cells induces bone morphogenetic protein 6 (BMP-6) via RelB activation; in turn, BMP-6 stimulates PCa cell proliferation via the interaction between Smad5 and β-catenin (28). In addition, WNT5A activates NF-κB signaling to induce MMP7 expression, thereby contributing to the invasion of TNBC cells (105). A decrease in chicken ovalbumin upstream promoter transcription factor II results in endocrinotherapy resistance in BCa cells by activating the noncanonical NF-κB pathway (106); whereas, fucoxanthin appears to be able to reverse BCa endocrinotherapy resistance by suppressing RelB activation (107). Overexpression of aryl hydrocarbon receptor (AhR) leads to the activation of RelB, in turn upregulating IL-8 expression in BCa cells (108,109). Ribonucleotide reductase M2 (RRM2) leads to increased RelB activity, thereby endowing tamoxifen resistance due to the upregulation of Bcl-2 in BCa cells (110). Overall, NF-κB functions as a master switch, changing PCa/BCa from an AR/ER-positive phenotype to an AR/ER-negative phenotype (Fig. 3).

NF-κB regulates a series of genes relevant to endocrinotherapy resistance. Particularly, it has been widely recognized that both canonical and noncanonical NF-κB pathways are vital for resistance to hormone receptor-targeted treatment in PCa and BCa (52,53,58,60,111). As important NF-κB-regulated proteins, Bcl-2, cyclin D1, IL-6 and IL-8 appeared to be critical for endocrinotherapy resistance in both PCa and BCa. The main NF-κB regulated proteins associated with endocri- notherapy resistance are summarized in Fig. 4.

Since NF-κB contributes to endocrinotherapy resistance in PCa and BCa, NF-κB-targeted therapy has frequently been applied to enhance endocrinotherapy. Nitric oxide donors sensitize Trail-mediated apoptosis via inhibition of Bcl-xL through inactivation of NF-κB (137). IL-6, a NF-κB-regulated cytokine, contributes to androgen-independent PCa progression. Inhibition of IL-6 enhances the sensitivity of PCa to docetaxel (138). NF-κB activation in ARVs associated with CRPC leads to anti-androgen therapy resistance. Repression of NF-κB enhances the efficiency of hormone therapy (59). Notably, Wedelia chinensis herbal extract has been shown not merely to inhibit AR activity in androgen-dependent PCa, but also to suppress the expression of IKKα/β phosphorylation in hormone-independent PCa cells (139). In BCa, NSC35446, a hydrochloride salt compound, is able to inhibit anti-estrogenic tumor growth and reverse antiestrogen resistance by targeting NF-κB (140). Additionally, ivermectin reverses chemotherapeutic resistance via suppression of NF-κB-activated P-gp expression (141). Importantly, a number of compounds appear to efficiently treat both aggressive PCa and BCa via repression of NF-κB-mediated transcriptional activation. Curcumin, an inhibitor of the NF-κB canonical pathway, is able to inhibit the hormone-mediated invasion of BCa (142). The combination of curcumin and bicalutamide enhances the growth inhibition of androgen-independent PCa cells (143), while 1a,25-dihydroxyvitamin D3 has been reported to repress the NF-κB noncanonical pathway, which strongly reduces the growth of drug-resistant BCa cells and enhances the radiosensitivity of PCa cells (144,145). Parthenolide, a native compound that functions as an NF-κB repressor, has been shown to restore the sensitivity of tamoxifen to endocrine-resistant BCa cells and to enhance PCa cell radiosensitivity (146-148).

Endocrinotherapy resistance and tumor relapse are major challenges in treating advanced PCa and BCa. The progression from hormone-dependence to hormone-independence has been widely recognized to be one of main causes of endocrinotherapy resistance. Therefore, the molecular basis for the failure of treatments targeting AR or ER has been well investigated. This review reorganized the molecular mechanisms underlining endocrinotherapy resistance and concluded that NF-κB is the most important transcription regulator in activating the expression of a series of genes, leading to the acquisition of the endocrinotherapy resistance. In the majority of cases, NF-κB functionally substitutes AR or ER in transcriptional regulation for sustaining tumor cell survival and proliferation, by activating a different set of genes when the efficacy of AR/ER-targeted treatments declines. It should be noted, however, the inverse association between AR/ER and NF-κB is not persistent during the progression of PCa and BCa; in particular, a few case studies have demonstrated that RelA can cooperate with AR in transcriptional regulation when androgen deprivation treatment fails (103). Additionally, although the NF-κB pathway is thought to serve as a key mechanism underlying endocrinotherapy resistance, other signaling pathways, such as Myc, Stat3 and Wnt, also play regulatory roles in the acquisition of therapeutic resistance. Furthermore, NF-κB also plays a crucial role in the radioresistance of PCa and BCa through upregulation of antioxidant and antiapoptotic proteins, including MnSOD and Bcl-2 (149).

The present review also outlined that several upstream signaling pathways engage to trigger the NF-κB pathway; in particular, PI3K-AKT upstream signaling activates the NF-κB pathway in response to oxidative stress and inflammatory stimulation. Importantly, the cytokine/chemokine-NF-κB signaling feed-forward loop is indispensable for the acquisition of endocrinotherapy resistance. It was recently concluded that TGF-β, IL-6, IL-8 and TNF-α are the most important cytokines associated with multidrug resistance in BCa (150). These four cytokines are typical NF-κB-regulated proteins, and increased levels of inflammation in turn activate the NF-κB pathway, which promotes endocrinotherapy resistance.

Distant organ metastasis associated with multidrug resistance precludes successful treatment. A myriad of studies have demonstrated that RelA-activated canonical NF-κB pathway is critical for cancer progression and therapeutic resistance (82,103,110,124,151-153). However, the effect of the RelB-activated noncanonical NF-κB pathway is underestimated. Indeed, RelA can upregulate RelB, leading to sustained long-term NF-κB activity in cancer progression (76). Since the function of RelA is essential for normal physiological development, the failure of anticancer treatment by targeting RelA may be caused by either low therapeutic efficacy or unexpected side effects. It has been demonstrated that RelB is uniquely expressed at a high level in advanced PCa, which contributes to therapeutic resistance (149,154). Accordingly, blockage of RelB nuclear translocation has the effect of reversing resistance to treatment in AR-negative PCa (155). Thus, the inactivation of the noncanonical NF-κB pathway may provide a promising approach to the treatment of advanced PCa and BCa when AR/ER-targeted therapeutic efficiency declines.

In summary, this review emphasized the importance of NF-κB in the acquisition of endocrinotherapy resistance in PCa and BCa, suggesting that inhibition of the NF-κB pathway may overcome endocrinotherapy resistance and should be beneficial in developing comprehensive treatment strategies to control malignant PCa and BCa. In addition to the well-documented canonical NF-κB pathway, the noncanonical NF-κB pathway remains to be fully elucidated. Emerging evidence predicts that RelB may exert an even greater effect than RelA on metastasis and therapeutic resistance, based on its capacity for maintaining NF-κB activity. Of further interest, therefore, is why and how the noncanonical NF-κB pathway contributes to cancer progression and therapeutic resistance. To that end, this review is expected to shed light on future in-depth investigations into NF-κB function to advance the treatment of PCa/BCa therapeutic resistance.