The ovarian hormones estrogen and progesterone are master regulators of the development and function of a broad spectrum of human tissues, including the breast, reproductive and cardiovascular ...systems, brain and bone. Acting through the nuclear estrogen (ER) and progesterone receptors (PR), both play complex and essential coordinated roles in the extensive development of the lobular alveolar epithelial structures of the normal breast during puberty, the normal menstrual cycle and pregnancy. The past decade has seen major advances in understanding the mechanisms of action of estrogen and progesterone in the normal breast and in the delineation of the complex hierarchy of cell types regulated by ovarian hormones in this tissue. There is evidence for a role for both ER and PR in driving breast cancer, and both are favourable prognostic markers with respect to outcome. In this review, we summarize current knowledge of the mechanisms of action of ER and PR in the normal breast, and implications for the development and management of breast cancer.
The transcriptional effects of the ovarian hormone progesterone are pleiotropic, and binding to DNA of the nuclear progesterone receptor (PR), a ligand-activated transcription factor, results in ...diverse outcomes in a range of target tissues. To determine whether distinct patterns of genomic interaction of PR contribute to the cell specificity of the PR transcriptome, we have compared the genomic binding sites for PR in breast cancer cells and immortalized normal breast cells. PR binding was correlated with transcriptional outcome in both cell lines, with 60% of progestin-regulated genes associated with one or more PR binding regions. There was a remarkably low overlap between the PR cistromes of the two cell lines, and a similarly low overlap in transcriptional targets. A conserved PR binding element was identified in PR binding regions from both cell lines, but there were distinct patterns of enrichment of known cofactor binding motifs, with FOXA1 sites over-represented in breast cancer cell binding regions and NF1 and AP-1 motifs uniquely enriched in the immortalized normal line. Downstream analyses suggested that differential cofactor availability may generate these distinct PR cistromes, indicating that cofactor levels may modulate PR specificity. Taken together these data suggest that cell-specificity of PR binding is determined by the coordinated effects of key binding cofactors.
Epidemiological studies demonstrate associations between obstructive sleep apnea (OSA) and cancer incidence and mortality. The aim of this study was to measure OSA in women with breast (BC) or ...endometrial cancer (EC) and associations with clinico-pathological tumor variables.
In a cross sectional study, women with BC (12 months) or EC (3 months) post-diagnosis were recruited from cancer clinics. We collected demographic, anthropometric data, cancer stage, grade, histopathology and history of cancer treatment and all subjects had in-laboratory polysomnography. Sleepiness was assessed with the Epworth Sleepiness Scale (ESS). We compared anthropometric and polysomnographic data between cancer groups (unpaired t-tests), and assessed relationships between cancer characteristics and OSA variables (Fishers exact test). There were no significant differences between average age (BC:59.6±8.7 years(n = 50); EC:60.3±7.7 years(n = 37)), or ESS score (BC:6.4±4.4; EC 6.8±4.7; mean±SD; all p>0.2), however, BMI was higher in EC (BC: 29.7±7.9kgm-2; EC: 34.2±8.0 kgm-2; p<0.05). BC had longer sleep latency (BC:31.8±32minutes; EC:19.3±17.9 minutes), less Stage 3 sleep (BC:20.0±5.2%; EC:23.6±8.2%) and more REM sleep (BC:21.1±6.9%; EC: 16.6±5.7%), all p<0.05. EC had lower average awake and asleep oxygen saturation levels (BC: 95.6±1.3%; EC: 94.6±1.9% awake: BC: 94.8±2.1%; EC: 93.3±2.4% asleep; both p<0.05). Apnea-Hypopnea Index (AHI) (BC: 21.2(7.3-36.9) events/hr; EC: 15.7 (10-33.5) events/hour (median (interquartile range)) was not different p = 0.7), however, 58% and 57% of women with BC and EC respectively, had an AHI>15 events/hour. In this small sample size group, no significant associations (all p>0.1) were detected between OSA metrics and clinico-pathological tumor variables.
In postmenopausal women with breast or endometrial cancer there is high prevalence of OSA, with no association with specific tumor characteristics detected. Recognition of the high prevalence of OSA in women with cancer is important to recognise as it may impact on surgical risk and quality of life.
Nuclear receptors (NRs) have been targets of intensive drug development for decades due to their roles as key regulators of multiple developmental, physiological and disease processes. In breast ...cancer, expression of the estrogen and progesterone receptor remains clinically important in predicting prognosis and determining therapeutic strategies. More recently, there is growing evidence supporting the involvement of multiple nuclear receptors other than the estrogen and progesterone receptors, in the regulation of various processes important to the initiation and progression of breast cancer. We review new insights into the mechanisms of action of NRs made possible by recent advances in genomic technologies and focus on the emerging functional roles of NRs in breast cancer biology, including their involvement in circadian regulation, metabolic reprogramming and breast cancer migration and metastasis.
Progesterone (P), which signals through the P receptor (PR), is critical in normal development of the breast, but its signaling axis is also a major driver of breast cancer risk. Here we review ...recent advances in the understanding of P signaling in the normal human breast, with a focus on the importance of the balance between autocrine and paracrine signaling. To date, most data (which derive largely from mouse models or human breast cancer cell line studies) have demonstrated that the vast majority of PR+ cells appear to act as “sensor” cells, which respond to P stimulation by translating these hormonal cues into paracrine signals. However, growing evidence suggests that, dependent on the cellular context, P may also signal in an autocrine manner in a subset of cells in the normal mouse mammary gland and human breast. It has been suggested that it may be dysregulation of this autocrine signaling, resulting in a “switch” from a predominance of paracrine signaling to autocrine signaling in PR+ cells, which is an early event during breast tumorigenesis. This review summarizes current evidence in the literature that demonstrates the mechanisms through which P acts in the normal human breast, as well as highlighting the important questions that remain unanswered.
Reproductive history is the strongest risk factor for breast cancer after age, genetics and breast density. Increased breast cancer risk is entwined with a greater number of ovarian hormone-dependent ...reproductive cycles, yet the basis for this predisposition is unknown. Mammary stem cells (MaSCs) are located within a specialized niche in the basal epithelial compartment that is under local and systemic regulation. The emerging role of MaSCs in cancer initiation warrants the study of ovarian hormones in MaSC homeostasis. Here we show that the MaSC pool increases 14-fold during maximal progesterone levels at the luteal dioestrus phase of the mouse. Stem-cell-enriched CD49fhi cells amplify at dioestrus, or with exogenous progesterone, demonstrating a key role for progesterone in propelling this expansion. In aged mice, CD49fhi cells display stasis upon cessation of the reproductive cycle. Progesterone drives a series of events where luminal cells probably provide Wnt4 and RANKL signals to basal cells which in turn respond by upregulating their cognate receptors, transcriptional targets and cell cycle markers. Our findings uncover a dynamic role for progesterone in activating adult MaSCs within the mammary stem cell niche during the reproductive cycle, where MaSCs are putative targets for cell transformation events leading to breast cancer.
To examine the association between prior chlamydia and gonorrhoea infections and adverse obstetric outcomes.
Records of women resident in New South Wales, Australia with a singleton first birth ...during 1999-2008 were linked to chlamydia and gonorrhoea notifications using probabilistic linkage. Obstetric outcomes and potential confounders were ascertained from the birth record. Logistic regression, adjusted for potential confounders was used to estimate the association between a disease notification prior to the birth and adverse birth outcomes: spontaneous preterm birth (SPTB), small for gestational age (SGA) and stillbirth.
Among 354 217 women, 1.0% (n=3658) had a prior chlamydia notification; 0.06% (n=196) had a prior gonorrhoea notification. The majority of notifications (>80%) occurred before the estimated conception date. 4.1% of women had a SPTB, 12.1% had a SGA baby and 0.6% of women had a stillbirth. Among women with a prior chlamydia notification, the risk of SPTB and stillbirth was increased, aOR 1.17 (95% CI 1.01 to 1.37) and aOR 1.40 (95% CI 1.00 to 1.96) respectively but there was no association with SGA, aOR 0.99 (95% CI 0.89 to 1.09). For women with gonorrhoea the risks for SPTB, stillbirth and SGA were respectively aOR 2.50 (95%CI 1.39 to 4.50), 2.35 (95% CI 0.58 to 9.56) and 0.98 (95% CI 0.58 to 1.68). Among women with a prior chlamydia diagnosis, the risk of SPTB did not differ between women diagnosed >1 year prior to conception, within the year prior to conception or during the pregnancy, (p=0.9).
Sexually transmissible infections in pregnancy and the preconception period may be important in predicting pregnancy outcomes.
Triple-negative breast cancers (TNBC) lack expression of oestrogen, progesterone and HER2 receptors. The gene expression profiles of TNBCs are similar to those of breast tumours in women with BRCA1 ...mutations. Reports to date indicate that up to 20 % of TNBC patients harbour germline
BRCA
mutations; however, the prevalence of
BRCA
mutations in TNBC patients varies widely between countries and from study to study. We studied 774 women with triple-negative breast cancer, diagnosed on average at age 58.0 years. Samples of genomic DNA were provided by the Australian Breast Cancer Tissue Bank (ABCTB) (439 patients) and by the Department of Genetics and Pathology of the Pomeranian Medical University (335 patients). The entire coding regions and the exon–intron boundaries of
BRCA1
and
BRCA2
were amplified and sequenced by next-generation sequencing. We identified a BRCA1 or BRCA2 mutation in 74 of 774 (9.6 %) triple-negative patients. The mutation prevalence was 9.3 % in Australia and was 9.9 % in Poland. In both countries, the mean age of diagnoses of
BRCA1
mutation carriers was significantly lower than that of non-carriers, while the age of onset of
BRCA2
mutation carriers was similar to that of non-carriers. In the Australian cohort, 59 % of the mutation-positive patients did not have a family history of breast or ovarian cancer, and would not have qualified for genetic testing. The triple-negative phenotype should be added as a criterion to genetic screening guidelines.
The role of nuclear receptors in both the aetiology and treatment of breast cancer is exemplified by the use of the oestrogen receptor (ER) as a prognostic marker and treatment target. Treatments ...targeting the oestrogen signalling pathway are initially highly effective for most patients. However, for the breast cancers that fail to respond, or become resistant, to current endocrine treatments, the long-term outlook is poor. ER is a member of the nuclear receptor superfamily, comprising 48 members in the human, many of which are expressed in the breast and could be used as alternative targets in cases where current treatments are ineffective.
We used sparse canonical correlation analysis to interrogate potential novel nuclear receptor expression relationships in normal breast and breast cancer. These were further explored using whole transcriptome profiling in breast cancer cells after combinations of ligand treatments.
Using this approach, we discovered a tumour suppressive relationship between the mineralocorticoid receptor (MR) and retinoic acid receptors (RAR), in particular RARβ. Expression profiling of MR expressing breast cancer cells revealed that mineralocorticoid and retinoid co-treatment activated an expression program consistent with a reverse Warburg effect and growth inhibition, which was not observed with either ligand alone. Moreover, high expression of both MR and RARB was associated with improved breast cancer-specific survival.
Our study reveals a previously unknown relationship between MR and RAR in the breast, which is dependent on menopausal state and altered in malignancy. This finding identifies potential new targets for the treatment of breast cancers that are refractory to existing therapeutic options.
Low-grade serous ovarian carcinomas (LGSC) are Ras pathway-mutated, TP53 wild-type, and frequently associated with borderline tumors. Patients with LGSCs respond poorly to platinum-based chemotherapy ...and may benefit from pathway-targeted agents. High-grade serous carcinomas (HGSC) are TP53-mutated and are thought to be rarely associated with borderline tumors. We sought to determine whether borderline histology associated with grade 2 or 3 carcinoma was an indicator of Ras mutation, and we explored the molecular relationship between coexisting invasive and borderline histologies.
We reviewed >1,200 patients and identified 102 serous carcinomas with adjacent borderline regions for analyses, including candidate mutation screening, copy number, and gene expression profiling.
We found a similar frequency of low, moderate, and high-grade carcinomas with coexisting borderline histology. BRAF/KRAS alterations were common in LGSC; however, we also found recurrent NRAS mutations. Whereas borderline tumors harbored BRAF/KRAS mutations, NRAS mutations were restricted to carcinomas, representing the first example of a Ras oncogene with an obligatory association with invasive serous cancer. Coexisting borderline and invasive components showed nearly identical genomic profiles. Grade 2 cases with coexisting borderline included tumors with molecular features of LGSC, whereas others were typical of HGSC. However, all grade 3 carcinomas with coexisting borderline histology were molecularly indistinguishable from typical HGSC.
Our findings suggest that NRAS is an oncogenic driver in serous ovarian tumors. We demonstrate that borderline histology is an unreliable predictor of Ras pathway aberration and underscore an important role for molecular classification in identifying patients that may benefit from targeted agents.
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