Estrogens and Progestins Cooperatively Shift Breast Cancer Cell Metabolism.

Metabolic reprogramming remains largely understudied in relation to hormones in estrogen receptor (ER) and progesterone receptor (PR) positive breast cancer. In this study, we investigated how estrogens, progestins, or the combination, impact metabolism in three ER and PR positive breast cancer cell lines. We measured metabolites in the treated cells using ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS).

Breast Cancer Suppression by Progesterone Receptors Is Mediated by Their Modulation of Estrogen Receptors and RNA Polymerase III.

Greater than 50% of estrogen receptor (ER)-positive breast cancers coexpress the progesterone receptor (PR), which can directly and globally modify ER action to attenuate tumor growth. However, whether this attenuation is mediated only through PR-ER interaction remains unknown. To address this question, we assessed tumor growth in ER/PR-positive patient-derived xenograft models of breast cancer, where both natural and synthetic progestins were found to antagonize the mitogenic effects of estrogens.

Steroid Hormone Receptor Positive Breast Cancer Patient-Derived Xenografts.

The vast majority of breast cancers are positive for estrogen receptor (ER) and depend on estrogens for growth. These tumors are treated with a variety of ER-targeted endocrine therapies, although eventual resistance remains a major clinical problem. Other steroid hormone receptors such as progesterone receptor (PR) and androgen receptor (AR) are emerging as additional prospective targets in breast cancer.

The Obesity-Breast Cancer Conundrum: An Analysis of the Issues.

Breast cancer develops over a timeframe of 2-3 decades prior to clinical detection. Given this prolonged latency, it is somewhat unexpected from a biological perspective that obesity has no effect or reduces the risk for breast cancer in premenopausal women yet increases the risk for breast cancer in postmenopausal women. This conundrum is particularly striking in light of the generally negative effects of obesity on breast cancer outcomes, including larger tumor size at diagnosis and poorer prognosis in both pre- and postmenopausal women.

Premenopausal Obesity and Breast Cancer Growth Rates in a Rodent Model.

Obese premenopausal women with breast cancer have poorer prognosis for long term survival, in part because their tumors are larger at the time of diagnosis than are found in normal weight women. Whether larger tumor mass is due to obesity-related barriers to detection or to effects on tumor biology is not known. This study used polygenic models for obesity and breast cancer to deconstruct this question with the objective of determining whether cell autonomous mechanisms contribute to the link between obesity and breast cancer burden.

Impact of Weight Loss on Plasma Leptin and Adiponectin in Overweight-to-Obese Post Menopausal Breast Cancer Survivors.

Women who are obese at the time of breast cancer diagnosis have higher overall mortality than normal weight women and some evidence implicates adiponectin and leptin as contributing to prognostic disadvantage. While intentional weight loss is thought to improve prognosis, its impact on these adipokines is unclear. This study compared the pattern of change in plasma leptin and adiponectin in overweight-to-obese post-menopausal breast cancer survivors during weight loss.

Excess weight gain accelerates 1-methyl-1-nitrosourea-induced mammary carcinogenesis in a rat model of premenopausal breast cancer.

In contrast to the null effects generally reported, high-risk premenopausal women (Gail score ≥1.66) enrolled in the Breast Cancer Prevention P-1 Trial were recently reported to be at increased risk for breast cancer when overweight (HR = 1.59) or obese (HR = 1.

Weight change patterns and breast cancer risk: a brief review and analysis.

Body weight change is defined as one or more periods of weight gain or weight loss that can vary in terms of magnitude, timeframe over which the change(s) occurs, and the number of times the pattern changes. Epidemiological and clinical data provide evidence of increased lifetime risk for breast cancer due to adult weight gain and a reduction of risk with weight loss. These findings parallel the majority of preclinical carcinogenesis experiments in which caloric intake in excess of basal metabolic requirements in rodents permits the development of cancer in proportion to the level of caloric intake.

Metabolite profiling of a diverse collection of wheat lines using ultraperformance liquid chromatography coupled with time-of-flight mass spectrometry.

Genetic differences among major types of wheat are well characterized; however, little is known about how these distinctions affect the small molecule profile of the wheat seed. Ethanol/water (65% v/v) extracts of seed from 45 wheat lines representing 3 genetically distinct classes, tetraploid durum (Triticum turgidum subspecies durum) (DW) and hexaploid hard and soft bread wheat (T. aestivum subspecies aestivum) (BW) were subjected to ultraperformance liquid chromatography coupled with time-of-flight mass spectrometry (UPLC-TOF-MS).

KU135, a novel novobiocin-derived C-terminal inhibitor of the 90-kDa heat shock protein, exerts potent antiproliferative effects in human leukemic cells.

The 90-kDa heat shock protein (Hsp90) assists in the proper folding of numerous mutated or overexpressed signal transduction proteins that are involved in cancer. Consequently, there is considerable interest in developing chemotherapeutic drugs that specifically disrupt the function of Hsp90. Here, we investigated the extent to which a novel novobiocin-derived C-terminal Hsp90 inhibitor, designated KU135, induced antiproliferative effects in Jurkat T-lymphocytes.

Characterization of a novel novobiocin analogue as a putative C-terminal inhibitor of heat shock protein 90 in prostate cancer cells.

Purpose: Hsp90 is important in the folding, maturation and stabilization of pro-tumorigenic client proteins and represents a viable drug target for the design of chemotherapies. Previously, we reported the development of novobiocin analogues designed to inhibit the C-terminal portion of Hsp90, which demonstrated the ability to decrease client protein expression. We now report the characterization of the novel novobiocin analogue, F-4, which demonstrates improved cytotoxicity in prostate cancer cell lines compared to the N-terminal inhibitor, 17-AAG.