Molecular Biology and Genetics / Moleküler Biyoloji ve Genetik
Permanent URI for this collectionhttps://hdl.handle.net/11147/9
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Article Citation - WoS: 90Citation - Scopus: 94Progesterone and Wnt4 Control Mammary Stem Cells Via Myoepithelial Crosstalk(John Wiley and Sons Inc., 2015) Rajaram, Renuga Devi; Buric, Duje; Caikovski, Marian; Ayyanan, Ayyakkannu; Rougemont, Jacques; Shan, Jingdong; Vainio, Seppo J.; Yalçın Özuysal, Özden; Brisken, CathrinOvarian hormones increase breast cancer risk by poorly understood mechanisms. We assess the role of progesterone on global stem cell function by serially transplanting mouse mammary epithelia. Progesterone receptor (PR) deletion severely reduces the regeneration capacity of the mammary epithelium. The PR target, receptor activator of Nf-κB ligand (RANKL), is not required for this function, and the deletion of Wnt4 reduces the mammary regeneration capacity even more than PR ablation. A fluorescent reporter reveals so far undetected perinatal Wnt4 expression that is independent of hormone signaling. Pubertal and adult Wnt4 expression is specific to PR+ luminal cells and requires intact PR signaling. Conditional deletion of Wnt4 reveals that this early, previously unappreciated, Wnt4 expression is functionally important. We provide genetic evidence that canonical Wnt signaling in the myoepithelium required PR and Wnt4, whereas the canonical Wnt signaling activities observed in the embryonic mammary bud and in the stroma around terminal end buds are independent of Wnt4. Thus, progesterone and Wnt4 control stem cell function through a luminal-myoepithelial crosstalk with Wnt4 acting independent of PR perinatally. Synopsis This paper ascribes a new role for Wnt4 in pre-pubertal mammary gland development while revealing luminal cells to respond to Wnt activation. During regeneration, Wnt4 interacts with progesterone receptor signaling, correcting previous notions on RANKL signaling in this context. Wnt4 is an essential control factor for mammary epithelial stem cell function. RANKL is not required for mammary gland regeneration potential. Wnt4 activates canonical Wnt signaling in the basal/myoepithelial compartment. Progesterone receptor signaling is required for mammary epithelial Wnt4 expression already during puberty. This paper ascribes a new role for Wnt4 in pre-pubertal mammary gland development while revealing luminal cells to respond to Wnt activation. During regeneration, Wnt4 interacts with progesterone receptor signaling, correcting previous notions on RANKL signaling in this context.Article Citation - WoS: 156Citation - Scopus: 163Progesterone/Rankl Is a Major Regulatory Axis in the Human Breast(American Association for the Advancement of Science, 2013) Tanos, Tamara; Sflomos, George; Echeverria, Pablo C.; Ayyanan, Ayyakkannu; Gutierrez, Maria; Delaloye, Jean-Francois; Raffoul, Wassim; Fiche, Maryse; Dougall, William; Schneider, Pascal; Yalçın Özuysal, Özden; Brisken, CathrinEstrogens and progesterones are major drivers of breast development but also promote carcinogenesis in this organ. Yet, their respective roles and the mechanisms underlying their action in the human breast are unclear. Receptor activator of nuclear factor kB ligand (RANKL) has been identified as a pivotal paracrine mediator of progesterone function in mouse mammary gland development and mammary carcinogenesis. Whether the factor has the same role in humans is of clinical interest because an inhibitor for RANKL, denosumab, is already used for the treatment of bone disease and might benefit breast cancer patients. We show that progesterone receptor (PR) signaling failed to induce RANKL in PR + breast cancer cell lines and in dissociated, cultured breast epithelial cells. In clinical specimens from healthy donors and intact breast tissue microstructures, hormone response was maintained and RANKL expression was under progesterone control, which increased RNA stability. RANKL was sufficient to trigger cell proliferation and was required for progesterone-induced proliferation. The findings were validated in vivo where RANKL protein expression in the breast epithelium correlated with serum progesterone levels and the protein was expressed in a subset of luminal cells that express PR. Thus, important hormonal control mechanisms are conserved across species, making RANKL a potential target in breast cancer treatment and prevention. Copyright 2013 by the American Association for the Advancement of Science; all rights reserved.Article Citation - WoS: 103Citation - Scopus: 112Perinatal Exposure To Bisphenol a Increases Adult Mammary Gland Progesterone Response and Cell Number(The Endocrine Society, 2011) Ayyanan, Ayyakkannu; Laribi, Ouahiba; Schuepbach-Mallepell, Sonia; Schrick, Christina; Gutierrez, Maria; Tanos, Tamara; Lefebvre, Gregory; Rougemont, Jacques; Yalçın Özuysal, Özden; Brisken, CathrinBisphenol A [BPA, 2,2,-bis (hydroxyphenyl) propane] is one of the highest-volume chemicals produced worldwide. It is detected in body fluids of more than 90% of the human population. Originally synthesized as an estrogenic compound, it is currently utilized to manufacture food and beverage containers resulting in uptake with food and drinks. There is concern that exposure to low doses of BPA, defined as less than or equal to 5 mg/kg body weight /d, may have developmental effects on various hormone-responsive organs including the mammary gland. Here, we asked whether perinatal exposure to a range of low doses of BPA is sufficient to alter mammary gland hormone response later on in life, with a possible impact on breast cancer risk. To mimic human exposure, we added BPA to the drinking water of C57/Bl6 breeding pairs. Analysis of the mammary glands of their daughters at puberty showed that estrogen-dependent transcriptional events were perturbed and the number of terminal end buds, estrogen-induced proliferative structures, was altered in a dose-dependent fashion. Importantly, adult females showed an increase in mammary epithelial cell numbers comparable to that seen in females exposed to diethylbestrol, a compound exposure to which was previously linked to increased breast cancer risk. Molecularly, the mRNAs encoding Wnt-4 and receptor activator of nuclear factor kB ligand, two key mediators of hormone function implicated in control of mammary stem cell proliferation and carcinogenesis, showed increased induction by progesterone in the mammary tissue of exposed mice. Thus, perinatal exposure to environmentally relevant doses of BPA alters long-term hormone response that may increase the propensity to develop breast cancer. © 2011 by The Endocrine Society.