Rosalia Simmen

University of Arkansas for Medical Sciences | UAMS · Department of Physiology and Cell Biology

CONTEXT Progesterone (P) resistance is a hallmark of endometriosis but the underlying mechanism(s) for loss of P-sensitivity leading to lesion establishment remains poorly understood. OBJECTIVE To evaluate the association between Notch-1 signaling activation and P-resistance in the progression of endometriosis. DESIGN Case-control study; archived...

Metformin (MET) is increasingly implicated in reducing the incidence of multiple cancer types in patients with diabetes. However, similar effects of MET in non-diabetic women with endometrial cancer (EC) remain unknown. In a pilot study, obese non-diabetic women diagnosed with type 1, grade 1/2 EC, and consenting to participate were randomly assign...

Metformin (MET) constitutes the first-line treatment against type 2 diabetes. Growing evidence linking insulin resistance and cancer risk has expanded the therapeutic potential of MET to several cancer types. However, the oncostatic mechanisms of MET are not well understood. MET has been shown to promote the expression of progesterone receptor (PGR...

Epidemiological studies inversely associate body mass index (BMI) with breast cancer risk in premenopausal women, but the pathophysiological linkage remains ill-defined. Despite the documented relevance of the ‘local’ environment to breast cancer progression and the well-accepted differences in transcriptome and metabolic properties of anatomically...

Endometriosis (ENDO) is a chronic estrogen-dependent gynecological condition that affects reproductive-age women, causing pelvic pain, infertility, and increased risk for ovarian cancer. Diabetes mellitus (DM) is a metabolic disease with significant morbidity and mortality and rising incidence worldwide. The occurrence of DM among ENDO patients rem...

Malic Enzyme 1 (ME1) supports lipogenesis, cholesterol synthesis, and cellular redox potential by catalyzing the decarboxylation of L-malate to pyruvate, and the concomitant reduction of NADP to NADPH. We examined the contribution of ME1 to the development of obesity by provision of an obesogenic diet to C57BL/6 wild type (WT) and MOD-1 (lack ME1 p...

Obesity, oxidative stress, and inflammation are risk factors for hepatocellular carcinoma (HCC). We examined, in mice, the effects of Krüppel-like factor 9 (KLF9) knockout on: adiposity, hepatic and systemic oxidative stress, and hepatic expression of pro-inflammatory and NOX/DUOX family genes, in a high-fat diet (HFD) context. Male and female Klf9...

Endometriosis is a chronic, estrogen-dependent gynecologic disorder that affects reproductive-aged women and to a lesser extent, post-menopausal women on hormone therapy. The condition is associated with systemic and local immune dysfunctions. While its underlying mechanisms remain poorly understood, endometriosis has a genetic component and propen...

Diabetes (DM) is a disease with significant morbidity and mortality and is a major public health problem worldwide. Endometriosis (ENDO) is a chronic estrogen-dependent gynecological condition that affects ~10% of reproductive-age women, causes debilitating pain and infertility, and carries an increased risk for ovarian cancer. Little is known abou...

Malic enzyme 1 (ME1) is a cytosolic protein that catalyzes the conversion of malate to pyruvate while concomitantly generating NADPH from NADP. Early studies identified ME1 as a mediator of intermediary metabolism primarily through its participatory roles in lipid and cholesterol biosynthesis. ME1 was one of the first identified insulin-regulated g...

Obesity is a major risk factor for many chronic diseases including postmenopausal breast cancer. Paradoxically, breast cancer susceptibility is inversely linked to obesity in pre-menopausal women. Adipose tissues are active endocrine organs that play major roles in tumor development and progression; however, fat depots at different anatomical sites...

Type 1 diabetes mellitus and endometriosis separately affect millions of women worldwide. Reproductive-age women diagnosed with type 1 diabetes may also suffer from endometriosis, but the asymptomatic pre-clinical period of highly variable duration for each condition can lead to challenges in the timely recognition of co-morbid disease onset and mi...

Endometriosis is a chronic gynecologic disorder that affects ~10% of adolescent girls and premenopausal women. The condition, classically defined as the presence of endometrial glands and stroma outside of the uterine cavity, is multifactorial and highly recurrent, and causes considerable morbidities that can significantly diminish the quality of l...

Colorectal cancer (CRC) is the third leading cause of cancer‐associated deaths in the USA. CRC has significant metabolic underpinnings but the connections between metabolic dysregulation and CRC remain elusive. Our laboratory studies the metabolic pathways involving Malic Enzyme 1 ( ME1 ), the cytosolic enzyme that provides NADPH for fatty acid and...

Abstract Cytosolic Malic Enzyme (ME1) provides reduced NADP for anabolism and maintenance of redox status. To examine the role of ME1 in tumor genesis of the gastrointestinal tract, we crossed mice having augmented intestinal epithelial expression of ME1 (ME1-Tg mice) with ApcMin/+ mice to obtain male ApcMin/+/ME1-Tg mice. ME1 protein levels were s...

Endometriosis is a chronic inflammatory condition that may cause pelvic pain, dysmenorrhea, and/or infertility in women of reproductive age. While treatments may include medical or surgical management, the majority of therapeutic options are non-curative, and women may experience longstanding pain and/or disability. In general, chronic diseases are...

Metabolic stress in the early-life environment as a consequence of maternal overnutrition and obesity leads to an increased risk of adult metabolic syndrome in offspring. Given the greater risk for cancer development at a number of tissue sites for obese individuals, exposure of the highly developmentally “plastic” fetus and neonate to a dysregulat...

Background: We previously reported that dietary intake of shiitake mushroom (SM; Lentinus edodes) decreased serum concentrations of polar lipids in male rats. Objective: This study evaluated the dietary effects of SM on serum cholesterol-related and serum antioxidant indexes in rats of both sexes. Methods: Sprague-Dawley rats [38 dams and thei...

The emerging links between breast cancer and metabolic dysfunctions spawned by the obesity pandemic predict a disproportionate early disease onset in successive generations. Moreover, sensitivity to chemotherapeutic agents may be influenced by the patient's metabolic status to affect disease outcome. Maternal metabolic stress as a determinant of dr...

Enhanced inflammation and reduced apoptosis sustain the growth of endometriotic lesions. Alterations in the expression of estrogen receptor (ER) α and β accompany the conversion of resident endometrial cells within the normal uterine environment to ectopic lesions located in extra-uterine sites. Recent studies highlighted in this focused review lin...

Endometriosis is a benign gynecological condition that causes considerable morbidity due to associated infertility, debilitating pelvic pain and inflammatory dysfunctions. Diet is a highly-modifiable risk factor for many chronic diseases but its contribution to endometriosis has not been extensively investigated, due partly to the paradoxical inver...

Colorectal cancer (CRC) is a disease whose genesis may include metabolic dysregulation. Cancer stem cells are attractive targets for therapeutic interventions since their aberrant expansion may underlie tumor initiation, progression, and recurrence. To investigate the actions of metabolic regulators on cancer stem cell-like cells (CSC) in CRC, we d...

Expression of the transcription factor Krüppel-like factor 9 (KLF9) is frequently reduced in colorectal cancers, although a tumor suppressive role has not been established. To determine if KLF9 suppresses intestinal adenoma formation, we generated mice of distinct Klf9 genotypes in the background of the Apc(Min/+) mouse and compared their adenoma b...

Krüppel-like factor (KLF) 13 and the closely-related KLF9 are members of the Sp/KLF family of transcription factors that have collectively emerged as essential regulators of tissue development, differentiation, proliferation, and programmed cell death. Steroid hormone-responsive tissues express multiple KLFs which are linked to progesterone recepto...

Female reproductive tract pathologies arise largely from dysregulation of estrogen and progesterone receptor signaling leading to aberrant cell proliferation, survival and differentiation. The signaling pathways orchestrated by these nuclear receptors are complex, require the participation of many nuclear proteins serving as key binding partners or...

The small intestine participates in lipid digestion, metabolism and transport. Cytosolic malic enzyme 1 (ME1) is an enzyme that generates NADPH used in fatty acid and cholesterol biosynthesis. Previous work has correlated liver and adipose ME1 expression with susceptibility to obesity and diabetes; however, the contributions of intestine-expressed...

Context: Late-term pregnancy may lead to maternal and neonatal morbidity and mortality. Mice null for the progesterone receptor co-regulator Krüppel-like Factor 9 (KLF9) exhibit delayed parturition and increased incidence of neonatal deaths. Objective: Our aim is to evaluate the contribution of myometrial KLF9 to human parturition. Design: Myo...

Many adult chronic diseases are thought to be influenced during early life by maternal nutrition; however, the underlying mechanisms remain largely unknown. Obesity-related diseases may be due partly to high fat consumption. Herein we evaluated mammary tumor risk in female MMTV-Wnt1-transgenic (Tg) offspring exposed to high fat (HFD) or control (CD...

Endometriosis, a steroid hormone-dependent disease characterized by aberrant activation of estrogen receptor signaling and progesterone resistance, remains intractable due to the complexity of the pathways underlying its manifestation. We previously showed that eutopic endometria of women with endometriosis exhibit lower expression of Krüppel-like...

Adipocytes from white adipose tissue secrete cytokines and other bioactive proteins which are collectively termed adipokines. Adiposity has been linked with increased breast cancer risk as adipokines secreted by adipocytes significantly affect epithelial cells from which breast cancer arises. Measurement of extracellular adipokine concentrations th...

A hallmark of cigarette smoking is a shift in the protease/antiprotease balance, in favor of protease activity. However, it has recently been shown that smokers have increased expression of a key antiprotease, secretory leukoprotease inhibitor (SLPI), yet the mechanisms involved in SLPI transcriptional regulation and functional activity of SLPI rem...

Diet is highly linked to breast cancer risk, yet little is known about its influence on mammary epithelial populations with distinct regenerative and hence, tumorigenic potential. To investigate this, we evaluated the relative frequency of lineage-negative CD29(hi)CD24(+), CD29(lo)CD24(+) and CD29(hi)Thy1(+)CD24(+) epithelial subpopulations in pre-...

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Colorectal cancer (CRC) remains the third leading cause of cancer-related deaths in the United States. Recent attention has focused on several members of the Kruppel-like family (KLF) of transcription factors in pathogenesis of CRC. Published studies in mouse models have d...

Thyroid hormones play a critical role in the growth and development of the alimentary tract in vertebrates. Their effects are mediated by nuclear receptors as well as the cell surface receptor integrin αVβ3. Systemic thyroid hormone levels are controlled via activation and deactivation by iodothyronine deiodinases in the liver and other tissues. Gi...

Mammary adipose tissue may contribute to breast cancer development and progression by altering neighboring epithelial cell behavior and phenotype through paracrine signaling. Dietary exposure to soy foods is associated with lower mammary tumor risk and reduced body weight and adiposity in humans and in rodent breast cancer models. Despite the sugge...

We have shown the lower growth rates of tumors that developed from Wnt1‐transgenic (Tg) offspring of dams consuming whole blueberry powder (3% BB) during pregnancy and lactation, compared to those of control (Casein) dams. Dietary exposure at post‐weaning through lifetime did not mimic the effects of early BB exposure. The basis for maternal BB eff...

Many adult chronic diseases might be programmed during early life by maternal nutritional history. Here, we evaluated effects of maternal high fat diet on mammary gland development and tumor formation in adult progeny. Female Wnt‐1 transgenic mice exposed to high fat (HFD, 45% kcal fat) or control Casein (CAS, 17% kcal fat) diets in utero and durin...

The increasing cognizance that diet (and lifestyle) can modify breast cancer risk and progression has motivated many breast cancer patients to take increasing personal control of the direction of their therapies after diagnosis and surgery. While this has certain advantages, including higher compliance to prescribed drugs and improvements in emotio...

Cells lining the respiratory tract are equipped with mechanisms that dampen the effects of oxidative stress. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a mediator involved in regulating oxidative stress. Recent data indicate Nrf2 also controls expression of secretory leukocyte protease inhibitor (SLPI). Sulforaphane (SFN), an isothiocyan...

Despite the well-accepted notion that early maternal influences persist beyond fetal life and may underlie many adult diseases, the risks imposed by the maternal environment on breast cancer development and underlying biological mechanisms remain poorly understood. Here, we investigated whether early exposure to blueberry [BB] via maternal diet alt...

Obesity and associated hormonal disturbances are risk factors for colon cancer. Cytosolic Malic Enzyme (ME1) generates NADPH used for lipogenesis in gastrointestinal (GI), liver and adipose tissues. We have reported that inclusion of soy protein isolate (SPI) in the diet lowered body fat content and colon tumor incidence of rats fed AIN-93G diet, w...

The ovarian hormones estrogen and progesterone promote uterine receptivity and successful pregnancy through their cognate receptors functioning in concert with context-dependent nuclear co-regulators. Previously, we showed that transcription factor Krüppel-like factor 9 (KLF9) is a progesterone receptor (PGR) co-activator in the uterus and mice nul...

Breast cancer is the leading cause of cancer deaths in women. Diet and lifestyle are major contributing factors to increased breast cancer risk. While mechanisms underlying dietary protection of mammary tumor formation are increasingly elucidated, there remains a dearth of knowledge on the nature and precise actions of specific bioactive components...

Mammary adiposity may contribute to breast cancer development and progression by releasing cytokines and other inflammatory mediators that promote mammary epithelial proliferation. We evaluated the effects of soy isoflavone genistein (GEN) on the adipogenic differentiation of a SV40‐immortalized mouse mammary stromal fibroblast like cells (MSF) tre...

Despite the well‐accepted notion of peri‐natal origins of adult diseases, the factors and regulatory mechanisms underlying breast cancer development remain unclear. Diet is a highly modifiable determinant of breast cancer risk, and the effects of the in utero nutritional environment persist beyond fetal life. We investigated whether in utero/ lacta...

Endometriosis is characterized by progesterone resistance and associated with infertility. Krüppel-like factor 9 (KLF9) is a progesterone receptor (PGR)-interacting protein, and mice null for Klf9 are subfertile. Whether loss of KLF9 expression contributes to progesterone resistance of eutopic endometrium of women with endometriosis is unknown. The...

Mammary stem cells are undifferentiated epithelial cells, which initiate mammary tumors and render them resistant to anticancer therapies, when deregulated. Diets rich in fruits and vegetables are implicated in breast cancer risk reduction, yet underlying mechanisms are poorly understood. Here, we addressed whether dietary factors selectively targe...

s: AACR International Conference on Frontiers in Cancer Prevention Research‐‐ Oct 22-25, 2011; Boston, MA Obesity and the associated hyperinsulinemia are major risk factors for colorectal cancer (CRC). The Fatty Acid Synthase (FASN) gene encodes the protein responsible for de novo synthesis of fatty acids. FASN mRNA and protein are insulin-induced...

An increasing body of evidence implicates obesity and the attendant hyperinsulinemia as major risk factors for human colorectal cancers. The lipogenic pathway supports growth and survival of colon cancer cells. In particular, inhibition of Fatty Acid Synthase (FASN) or Acetyl-CoA Carboxylase α (ACCα) induces apoptosis of colon cancer cells. The rel...

Estrogen (E) and Progesterone (P) actions in female reproductive tissue development and homeostasis are mediated by their cognate receptors (ESR, PGR) in concert with a whole host of context-dependent nuclear receptor co-regulators. While >200 of the latter proteins have now been identified, there is yet an incomplete mechanistic understanding of h...

Mammary stromal adipocytes constitute an active site for the synthesis of the adipokine, adiponectin (APN) that may influence the mammary epithelial microenvironment. The relationship between "local," mammary tissue-derived APN and breast cancer risk is poorly understood. Here, we identify a novel mechanism of APN-mediated signaling that influences...

The dramatic rise in worldwide prevalence of obesity has necessitated the search for more efficacious antiobesity strategies to counter the increased cancer risks in overweight and obese individuals. The mechanistic pathways linking obesity status with adult chronic diseases such as cancer remain incompletely understood. A growing body of evidence...

Endometrial cancer is the most commonly diagnosed female genital tract malignancy. Krüppel-like factor 9 (KLF9), a member of the evolutionarily conserved Sp family of transcription factors, is expressed in uterine stroma and glandular epithelium, where it affects cellular proliferation, differentiation, and apoptosis. Deregulated expression of a nu...