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    • WNT signaling is well recognized for its role

    2018-10-24

    WNT signaling is well recognized for its role in regulating stem and progenitor buy stavudine in diverse systems (Nusse et al., 2008). Elevated levels of β-catenin, indicative of aberrant WNT signaling, are reported in more than 50% of human breast carcinomas, correlate with poor prognosis, and are preferentially found in the aggressive triple-negative (ER−PR−HER2−) basal-like subtype (Geyer et al., 2011; Lin et al., 2000; Ryo et al., 2001). RANK signaling is also emerging as a significant variable in breast cancer (Schramek et al., 2010) with microarray data showing the highest levels of RANK in poor prognosis basal-like human breast cancers in comparison to other molecularly defined subtypes (Santini et al., 2011). Progesterone is likewise becoming increasingly recognized as a critical contributor to human breast cancer development, largely through lessons learned from increased breast cancer incidence in hormone replacement therapy trials with progestin combinations (Beral, 2003; Chlebowski et al., 2015; Joshi et al., 2015; Rossouw et al., 2002). A recent study also reported significantly higher levels of progesterone in BRCA1/2 mutation carriers who are at increased risk of ovarian and breast cancer, suggesting a progesterone influence on premenopausal breast cancer risk (Widschwendter et al., 2013). RANKL and WNT signaling are known to be downstream effectors of progesterone (Beleut et al., 2010; Brisken et al., 2000; Fata et al., 2000; Joshi et al., 2010; Rajaram et al., 2015), but their underlying mechanism of action on distinct cellular targets in the normal and neoplastic mammary gland remains poorly understood. We now demonstrate that RANKL from ER+PR+ luminal epithelial cells acts on the mouse ER–PR– luminal alveolar progenitor compartment to activate RSPO1 and enable WNT responsiveness, resulting in the expansion of ER−PR− luminal alveolar progenitors and basal cells that jointly culminate in the generation of lobuloalveoli (Figure 6). Interestingly, RSPO1 has been shown to be required for alveolar formation in the mouse mammary gland, where its expression pattern during gestation paralleled that of Wnt4 (Chadi et al., 2009). RSPO1 enhances WNT signaling through its stabilizing effects on the WNT receptor complex and promotes the expansion of intestinal LGR5+ stem cells (de Lau et al., 2014). Recent work also shows its cooperation with WNT4 for mammary stem cell renewal (Cai et al., 2014). Here, we discover a crucial role for RANKL in inducing RSPO1 and engaging the WNT response in primitive mammary cells, thus enabling them to respond to progesterone. Given the widely documented role of WNT signals in controlling stem and progenitor cells in other tissues, our findings may prove to have broader relevance. The RANKL-RANK driven, WNT-responsive ER−PR− luminal progenitors in the mouse and RANK-expressing luminal progenitors that expand in the human breast during the progesterone-high menstrual phase appear to represent analogous, highly proliferative progenitors within lobuloalveolar units. Since lobuloalveoli are the most common site of mammary cancer development in both mouse and human, it is tempting to nominate this progenitor as a strong candidate for breast carcinogenesis. Targeting RANK signaling in clinical trials utilizing Denosumab, a fully human monoclonal antibody to RANKL, has proved effective in reducing skeletal-related events and bone metastasis in breast cancer patients (Stopeck et al., 2010). Thus, it may be important to test the therapeutic capacity of Denosumab against primary breast cancer for treatment or prevention. However, in light of breast cancer heterogeneity and emerging RANK expression data, variable effects on different breast cancer subtypes and stages would also be anticipated to affect therapeutic outcomes. Since the WNT pathway is considered therapeutically elusive, RANK signaling blockade may also serve as a means to curtail WNT activity during breast pathogenesis.