Biomarkers can be used for diagnosis, prognosis, and prediction in targeted therapy. The estrogen receptor α (ERα) and human epidermal growth factor receptor 2 (HER2) are standard biomarkers used in breast cancer for guiding disease treatment. The androgen receptor (AR), a nuclear hormone receptor, contributes to the development and progression of prostate tumors and other cancers. With increasing evidence to support that AR plays an essential role in breast cancer, AR has been considered a useful biomarker in breast cancer, depending on the context of breast cancer sub-types. The existing survival analyses suggest that AR acts as a tumor suppressor in ER + ve breast cancers, serving as a favorable prognostic marker. However, AR functions as a tumor promoter in ER-ve breast cancers, including HER2 + ve and triple-negative (TNBC) breast cancers, serving as a poor prognostic factor. AR has also been shown to be predictive of the potential of response to adjuvant hormonal therapy in ER + ve breast cancers and to neoadjuvant chemotherapy in TNBC. However, conflicting results do exist due to intrinsic molecular differences between tumors and the scoring method for AR positivity. Applying AR expression status to guide treatment in different breast cancer sub-types has been suggested. In the future, AR will be a feasible biomarker for breast cancer. Clinical trials using AR antagonists in breast cancer are active. Targeting AR alone or other therapeutic agents provides alternatives to existing therapy for breast cancer. Therefore, AR expression will be necessary if AR-targeted treatment is to be used.

The androgen receptor (AR) is a steroid hormone receptor widely detected in breast cancer. Evidence suggests that the AR might be a tumor suppressor in estrogen receptor alpha-positive (ERα+ve) breast cancer but a tumor promoter in estrogen receptor alpha-negative (ERα-ve) breast cancer. Modulating AR activity could be a potential strategy for treating breast cancer. For ERα+ve breast cancer, activation of the AR had been demonstrated to suppress the disease. In contrast, for ERα-ve breast cancer, blocking the AR could confer better prognosis to patients. These studies support the feasibility of utilizing AR modulators as anti-cancer drugs for different subtypes of breast cancer patients. Nevertheless, several issues still need to be addressed, such as the lack of standardization in the determination of AR positivity and the presence of AR splice variants. In future, the inclusion of the AR status in the breast cancer report at the time of diagnosis might help improve disease classification and treatment decision, thereby providing additional treatment strategies for breast cancer.

Breast cancer is a heterogeneous disease. Around 70% of breast cancers are estrogen receptor-positive (ER+ve), with tamoxifen being most commonly used as an adjuvant treatment to prevent recurrence and metastasis. However, half of the patients will eventually develop tamoxifen resistance. The overexpression of c-MYC can drive the development of ER+ve breast cancer and confer tamoxifen resistance through multiple pathways. One key mechanism is to enhance ribosome biogenesis, synthesising mature ribosomes. The over-production of ribosomes sustains the demand for proteins necessary to maintain a high cell proliferation rate and combat apoptosis induced by therapeutic agents. c-MYC overexpression can induce the expression of eIF4E that favours the translation of structured mRNA to produce oncogenic factors that promote cell proliferation and confer tamoxifen resistance. Either non-phosphorylated or phosphorylated eIF4E can mediate such an effect. Since ribosomes play an essential role in c-MYC-mediated cancer development, suppressing ribosome biogenesis may help reduce aggressiveness and reverse tamoxifen resistance in breast cancer. CX-5461, CX-3543 and haemanthamine have been shown to repress ribosome biogenesis. Using these chemicals might help reverse tamoxifen resistance in ER+ve breast cancer, provided that c-MYC-mediated ribosome biogenesis is the crucial factor for tamoxifen resistance. To employ these ribosome biogenesis inhibitors to combat tamoxifen resistance in the future, identification of predictive markers will be necessary.

Breast cancer is a heterogeneous disease. Tamoxifen is frequently used to treat ER-positive breast cancer. Our team has identified a novel splice variant of NCOR2, BQ323636.1 (BQ), that mediates tamoxifen resistance. However, the upstream factors that modulate BQ expression are not apparent. This study reveals that tamoxifen treatment causes induction of DNA damage which can enhance BQ expression. We show that DNA damage can activate the ATM/CHK2 and ATR/CHK1 signalling cascades and confirm that ATM/CHK2 signalling is responsible for enhancing the protein stability of BQ. siRNA or a small inhibitor targeting CHK2 resulted in the reduction in BQ expression through reduced phosphorylation and enhanced poly-ubiquitination of BQ. Inhibition of CHK2 by CCT241533 could reverse tamoxifen resistance in vitro and in vivo. Using clinical samples in the tissue microarray, we confirmed that high p-CHK2 expression was significantly associated with high nuclear BQ expression, tamoxifen resistance and poorer overall and disease-specific survival. In conclusion, tamoxifen treatment can enhance BQ expression in ER-positive breast cancer by activating the ATM/CHK2 axis. Targeting CHK2 is a promising approach to overcoming tamoxifen resistance in ER-positive breast cancer.

About 70% of breast cancer patients are oestrogen receptor-positive (ER +ve). Adjuvant endocrine therapy using tamoxifen (TAM) is an effective approach for preventing local recurrence and metastasis. However, around half of the patients will eventually develop resistance. Overexpression of BQ323636.1 (BQ) is one of the mechanisms that confer TAM resistance. BQ is an alternative splice variant of NCOR2. The inclusion of exon 11 generates mRNA for NCOR2, while the exclusion of exon 11 produces mRNA for BQ. The expression of SRSF5 is low in TAM-resistant breast cancer cells. Modulation of SRSF5 can affect the alternative splicing of NCOR2 to produce BQ. In vitro and in vivo studies confirmed that the knockdown of SRSF5 enhanced BQ expression, and conferred TAM resistance; in contrast, SRSF5 overexpression reduced BQ expression and, thus, reversed TAM resistance. Clinical investigation using a tissue microarray confirmed the inverse correlation of SRSF5 and BQ. Low SRSF5 expression was associated with TAM resistance, local recurrence and metastasis. Survival analyses showed that low SRSF5 expression was associated with poorer prognosis. We showed that SRPK1 can interact with SRSF5 to phosphorylate it. Inhibition of SRPK1 by a small inhibitor, SRPKIN-1, suppressed the phosphorylation of SRSF5. This enhanced the proportion of SRSF5 interacting with exon 11 of NCOR2, reducing the production of BQ mRNA. As expected, SRPKIN-1 reduced TAM resistance. Our study confirms that SRSF5 is essential for BQ expression. Modulating the activity of SRSF5 in ER +ve breast cancer will be a potential approach to combating TAM resistance.

BQ323636.1 (BQ), a splice variant of NCOR2, is associated with endocrine therapy resistance and poorer prognosis in ER-positive breast cancer. This study investigates the role of BQ in modulating lipid metabolism to support tumor growth. RNA sequencing of BQ-overexpressing breast cancer cells revealed significant enrichment of fatty acid metabolism pathways (hsa01212 and hsa00061; p < 0.05), with ACSL4 identified as a key target. We show that BQ disrupts the NCOR2-PPARγ interaction, leading to ACSL4 upregulation, which enhances fatty acid oxidation (FAO), acetyl-CoA by 1.8-fold, and ATP production by 2.5-fold to fuel tumor proliferation. BQ also upregulates FASN and SCD, increasing lipids. A metabolites study with mass spectrometry indicated that BQ overexpression increases the fatty acid amount from 47.97 nmol/10⁶ cells to 75.18 nmol/10⁶ cells in MCF7 and from 56.19 nmol/10⁶ cells to 95.37 nmol/10⁶ cells in ZR-75. BQ activates NRF2, which mitigates ROS-induced stress, promoting cell survival. Targeting ACSL4 with the inhibitor PRGL493 reduced ATP production and suppressed tumor growth in vitro and in vivo, without inducing apoptosis, suggesting a cytostatic effect. PRGL493 treatment can reduce BQ overexpressing tumors by 40% in the xenograft model. These results highlight BQ can serve as a transcriptional hub driving lipid metabolism via ACSL4 in breast cancer. Our findings suggest that ACSL4 inhibition could be a novel therapeutic strategy to overcome treatment resistance in high-BQ expressing ER-positive breast cancer.