Constitutive activation of RANK disrupts mammary cell fate leading to tumorigenesis

Pellegrini, Pasquale; Cordero, Álex; Gallego, Marta I.; Dougall, William C.; Muñoz, Purificacı́on; Pujana, Miguel Ángel; González‐Suárez, Eva

doi:10.1002/stem.1454

Cited by 44 publications

(66 citation statements)

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“…Our results suggest that neoadjuvant RANKL inhibition may be more efficient in reducing recurrence and metastasis than adjuvant treatment, as a significant reduction in the CSC population was observed on tumors treated at passage 1. Along with our previous data demonstrating that overactivation of RANK signaling at midgestation disrupts lactogenesis (12,39), current results suggest that RANK signaling regulates the balance between self-renewal and differentiation not only during mammary gland development but also in breast adenocarcinomas.…”

Section: Discussionsupporting

confidence: 85%

“…Our previous data showed that enhanced RANK activation promotes stemness in human and mouse mammary epithelia, leading to the accumulation of MaSC and progenitors (11,12,39). Importantly, now we demonstrate that inhibition of RANK signaling reduces CSC in invasive mammary tumors decreasing recurrence and metastasis, and induces tumor cell differentiation.…”

Section: Discussionsupporting

confidence: 62%

“…The decrease in Sca1 À cells upon RANK loss or inhibition and their enhanced mammosphere-forming and tumor-initiating potential demonstrate that this population is enriched in CSCs in the PyMT tumors, as shown in the MMTV-wnt model (47). A negative regulation of Sca1 þ by RANK has been observed during mammary gland development (12,34). The relevance of Sca1/Ly6a as a CSC marker in human luminal adenocarcinomas deserves further investigation.…”

Section: Discussionmentioning

confidence: 84%

“…Overexpression of RANKL's receptor, RANK in mammary epithelial cells enhances proliferation, impairs lactation, and induces the accumulation of mammary stem cells (MaSC) and progenitors (9)(10)(11)(12). In human adenocarcinomas, RANK is predominantly expressed in hormone receptor-negative (HR À ) tumors, supporting a progesterone-independent role.…”

Section: Introductionmentioning

confidence: 99%

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RANK Signaling Blockade Reduces Breast Cancer Recurrence by Inducing Tumor Cell Differentiation

et al. 2016

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RANK expression is associated with poor prognosis in breast cancer even though its therapeutic potential remains unknown. RANKL and its receptor RANK are downstream effectors of the progesterone signaling pathway. However, RANK expression is enriched in hormone receptor negative adenocarcinomas, suggesting additional roles for RANK signaling beyond its hormonedependent function. Here, to explore the role of RANK signaling once tumors have developed, we use the mouse mammary tumor virus-Polyoma Middle T (MMTV-PyMT), which mimics RANK and RANKL expression patterns seen in human breast adenocarcinomas. Complementary genetic and pharmacologic approaches demonstrate that therapeutic inhibition of RANK signaling drastically reduces the cancer stem cell pool, decreases tumor and metastasis initiation, and enhances sensitivity to chemotherapy. Mechanistically, genome-wide expression analyses show that anti-RANKL therapy promotes lactogenic differentiation of tumor cells. Moreover, RANK signaling in tumor cells negatively regulates the expression of Ap2 transcription factors, and enhances the Wnt agonist Rspo1 and the Sca1-population, enriched in tumor-initiating cells. In addition, we found that expression of TFAP2B and the RANK inhibitor, OPG, in human breast cancer correlate and are associated with relapse-free tumors. These results support the use of RANKL inhibitors to reduce recurrence and metastasis in breast cancer patients based on its ability to induce tumor cell differentiation. Cancer Res; 76(19); 5857-69. Ó2016 AACR.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

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RANK Signaling Blockade Reduces Breast Cancer Recurrence by Inducing Tumor Cell Differentiation

et al. 2016

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“…Precancerous BRCA1 mut/+ tissue harbors an aberrant population of luminal progenitor cells 1 , and deregulated progesterone signaling has been implicated in BRCA1-associated oncogenesis [2][3][4][5] . Coupled with the findings that tumor necrosis factor superfamily member 11 (TNFSF11; also known as RANKL) is a key paracrine effector of progesterone signaling [6][7][8][9][10] and that RANKL and its receptor TNFRSF11A (also known as RANK) contribute to mammary tumorigenesis [11][12][13] , we investigated a role for this pathway in the pre-neoplastic phase of BRCA1-mutation carriers. We identified two subsets of luminal progenitors (RANK + and RANK − ) in histologically normal tissue of BRCA1-mutation carriers and showed that RANK + cells are highly proliferative, have grossly aberrant DNA repair and bear a molecular signature similar to that of basal-like breast cancer.…”

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confidence: 99%

RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers

Nolan

Vaillant

Branstetter

et al. 2016

Nat Med

242

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Individuals who have mutations in the breast-cancer-susceptibility gene BRCA1 (hereafter referred to as BRCA1-mutation carriers) frequently undergo prophylactic mastectomy to minimize their risk of breast cancer. The identification of an effective prevention therapy therefore remains a 'holy grail' for the field. Precancerous BRCA1(mut/+) tissue harbors an aberrant population of luminal progenitor cells, and deregulated progesterone signaling has been implicated in BRCA1-associated oncogenesis. Coupled with the findings that tumor necrosis factor superfamily member 11 (TNFSF11; also known as RANKL) is a key paracrine effector of progesterone signaling and that RANKL and its receptor TNFRSF11A (also known as RANK) contribute to mammary tumorigenesis, we investigated a role for this pathway in the pre-neoplastic phase of BRCA1-mutation carriers. We identified two subsets of luminal progenitors (RANK(+) and RANK(-)) in histologically normal tissue of BRCA1-mutation carriers and showed that RANK(+) cells are highly proliferative, have grossly aberrant DNA repair and bear a molecular signature similar to that of basal-like breast cancer. These data suggest that RANK(+) and not RANK(-) progenitors are a key target population in these women. Inhibition of RANKL signaling by treatment with denosumab in three-dimensional breast organoids derived from pre-neoplastic BRCA1(mut/+) tissue attenuated progesterone-induced proliferation. Notably, proliferation was markedly reduced in breast biopsies from BRCA1-mutation carriers who were treated with denosumab. Furthermore, inhibition of RANKL in a Brca1-deficient mouse model substantially curtailed mammary tumorigenesis. Taken together, these findings identify a targetable pathway in a putative cell-of-origin population in BRCA1-mutation carriers and implicate RANKL blockade as a promising strategy in the prevention of breast cancer.

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Rankl Impairs Lactogenic Differentiation Through Inhibition of the Prolactin/Stat5 Pathway at Midgestation

et al. 2016

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Prolactin and progesterone both orchestrate the proliferation and differentiation of the mammary gland during gestation. Differentiation of milk secreting alveoli depends on the presence of prolactin receptor, the downstream Jak2-Stat5 pathway and the transcription factor Elf5. A strict regulation of Rank signaling is essential for the differentiation of the mammary gland and in particular for alveolar commitment. Impaired alveologenesis and lactation failure are observed in both, knockout and Rank overexpressing mice; however, the underlying molecular mechanism responsible for these phenotypes remains largely unknown. Using genome-wide expression analyses and functional studies, we show here that Rankl (RL) exposure leads to impaired secretory differentiation of alveolar cells not only in MMTV-RANK but also in wildtype (WT) mammary acini. Conversely, pharmacological blockage of Rank signaling at midgestation in WT mice leads to precocious and exacerbated lactogenesis. Mechanistically, RL negatively regulates Stat5 phosphorylation and Elf5 expression at the onset of lactogenesis. Continuous RL exposure leads to the expansion of basal and bipotent cells in WT and MMTV-RANK acini. Overall, we demonstrate that enhanced Rank signaling impairs secretory differentiation during pregnancy by inhibition of the prolactin/p-Stat5 pathway. STEM CELLS 2016;34:1027-1039 SIGNIFICANCE STATEMENTRank pathway is a key regulator of mammary stem cell fate and breast cancer. Rank governs the balance between mammary epithelial proliferation, survival and differentiation, acting as a key mediator of hormone action during mammary gland development. Rank loss but also Rank overexpression, lead to lactation failure. We and others have shown that in the early steps of alveologenesis, RANK pathway mediates progesterone driven proliferation and expansion of progenitors. Now we show that later in pregnancy, Rankl inhibits prolactin induced lactogenesis and terminal differentiation by interfering with Stat5 activation and expands basal and bipotent cells.

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Constitutive activation of RANK disrupts mammary cell fate leading to tumorigenesis

Cited by 44 publications

References 40 publications

RANK Signaling Blockade Reduces Breast Cancer Recurrence by Inducing Tumor Cell Differentiation

RANK Signaling Blockade Reduces Breast Cancer Recurrence by Inducing Tumor Cell Differentiation

RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers

Rankl Impairs Lactogenic Differentiation Through Inhibition of the Prolactin/Stat5 Pathway at Midgestation

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