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Breast Cancer (Tokyo, Japan) Jul 2024Triple-negative breast cancer (TNBC) is a highly heterogeneous tumor lacking estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor... (Review)
Review
Triple-negative breast cancer (TNBC) is a highly heterogeneous tumor lacking estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. It has higher aggressiveness and metastasis than other subtypes, with limited effective therapeutic strategies, leading to a poor prognosis. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway is prevalently over-activated in human cancers and contributes to breast cancer (BC) growth, survival, proliferation, and angiogenesis, which could be an interesting therapeutic target. This review summarizes the PI3K/AKT/mTOR signaling pathway activation mechanism in TNBC and discusses the relationship between its activation and various TNBC subtypes. We also report the latest clinical studies on kinase inhibitors related to this pathway for treating TNBC. Our review discusses the issues that need to be addressed in the clinical application of these inhibitors.
Topics: Humans; Triple Negative Breast Neoplasms; TOR Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Female; Phosphatidylinositol 3-Kinases; Molecular Targeted Therapy; Protein Kinase Inhibitors; MTOR Inhibitors; Antineoplastic Agents
PubMed: 38630392
DOI: 10.1007/s12282-024-01567-5 -
Journal For Immunotherapy of Cancer Jun 2023Progress in breast cancer (BC) research relies on the availability of suitable cell lines that can be implanted in immunocompetent laboratory mice. The best studied...
BACKGROUND
Progress in breast cancer (BC) research relies on the availability of suitable cell lines that can be implanted in immunocompetent laboratory mice. The best studied mouse strain, C57BL/6, is also the only one for which multiple genetic variants are available to facilitate the exploration of the cancer-immunity dialog. Driven by the fact that no hormone receptor-positive (HR) C57BL/6-derived mammary carcinoma cell lines are available, we decided to establish such cell lines.
METHODS
BC was induced in female C57BL/6 mice using a synthetic progesterone analog (medroxyprogesterone acetate, MPA) combined with a DNA damaging agent (7,12-dimethylbenz[a]anthracene, DMBA). Cell lines were established from these tumors and selected for dual (estrogen+progesterone) receptor positivity, as well as transplantability into C57BL/6 immunocompetent females.
RESULTS
One cell line, which we called B6BC, fulfilled these criteria and allowed for the establishment of invasive estrogen receptor-positive (ER) tumors with features of epithelial to mesenchymal transition that were abundantly infiltrated by myeloid immune populations but scarcely by T lymphocytes, as determined by single-nucleus RNA sequencing and high-dimensional leukocyte profiling. Such tumors failed to respond to programmed cell death-1 (PD-1) blockade, but reduced their growth on treatment with ER antagonists, as well as with anthracycline-based chemotherapy, which was not influenced by T-cell depletion. Moreover, B6BC-derived tumors reduced their growth on CD11b blockade, indicating tumor sustainment by myeloid cells. The immune environment and treatment responses recapitulated by B6BC-derived tumors diverged from those of ER TS/A cell-derived tumors in BALB/C mice, and of ER E0771 cell-derived and MPA/DMBA-induced tumors in C57BL/6 mice.
CONCLUSIONS
B6BC is the first transplantable HR BC cell line derived from C57BL/6 mice and B6BC-derived tumors recapitulate the complex tumor microenvironment of locally advanced HR BC naturally resistant to PD-1 immunotherapy.
Topics: Mice; Female; Animals; Progesterone; Epithelial-Mesenchymal Transition; Mice, Inbred BALB C; Mice, Inbred C57BL; Cell Line, Tumor; Carcinoma; Tumor Microenvironment
PubMed: 37344100
DOI: 10.1136/jitc-2023-007117 -
International Journal of Molecular... Dec 2023C11-oxy C and C11-oxy C steroids have been identified as novel steroids but their function remains unclear. This study aimed to investigate the pre-receptor regulation...
C11-oxy C and C11-oxy C steroids have been identified as novel steroids but their function remains unclear. This study aimed to investigate the pre-receptor regulation of C11-oxy steroids by 11β-hydroxysteroid dehydrogenase (11βHSD) interconversion and potential agonist and antagonist activity associated with the androgen (AR) and progesterone receptors (PRA and PRB). Steroid conversions were investigated in transiently transfected HEK293 cells expressing 11βHSD1 and 11βHSD2, while CV1 cells were utilised for agonist and antagonist assays. The conversion of C11-hydroxy steroids to C11-oxo steroids by 11βHSD2 occurred more readily than the reverse reaction catalysed by 11βHSD1, while the interconversion of C11-oxy C steroids was more efficient than C11-oxy C steroids. Furthermore, 11-ketodihydrotestosterone (11KDHT), 11-ketotestosterone (11KT) and 11β-hydroxydihydrotestosterone (11OHDHT) were AR agonists, while only progestogens, 11β-hydroxyprogesterone (11βOHP4), 11β-hydroxydihydroprogesterone (11βOHDHP4), 11α-hydroxyprogesterone (11αOHP4), 11α-hydroxydihydroprogesterone (11αOHDHP4), 11-ketoprogesterone (11KP4), 5α-pregnan-17α-diol-3,11,20-trione (11KPdione) and 21-deoxycortisone (21dE) exhibited antagonist activity. C11-hydroxy C steroids, 11βOHP4, 11βOHDHP4 and 11αOHP4 exhibited PRA and PRB agonistic activity, while only C11-oxo steroids, 11KP4 and 11-ketoandrostanediol (11K3αdiol) demonstrated PRB agonism. While no steroids antagonised the PRA, 11OHA4, 11β-hydroxytestosterone (11OHT), 11KT and 11KDHT exhibited PRB antagonism. The regulatory role of 11βHSD isozymes impacting receptor activation is clear-C11-oxo androgens exhibit AR agonist activity; only C11-hydroxy progestogens exhibit PRA and PRB agonist activity. Regulation by the downstream metabolites of active C11-oxy steroids at the receptor level is apparent-C11-hydroxy and C11-oxo metabolites antagonize the AR and PRB, progestogens the former, androgens the latter. The findings highlight the intricate interplay between receptors and active as well as "inactive" C11-oxy steroids, suggesting novel regulatory tiers.
Topics: Humans; Progesterone; Receptors, Progesterone; Androgens; Progestins; HEK293 Cells; Steroids; Receptors, Steroid; 11-beta-Hydroxysteroid Dehydrogenases
PubMed: 38203272
DOI: 10.3390/ijms25010101 -
Fertility and Sterility Oct 2020
Topics: Female; Gonadotropin-Releasing Hormone; Humans; Leiomyoma; Randomized Controlled Trials as Topic; Receptors, Progesterone; Uterine Neoplasms
PubMed: 32854931
DOI: 10.1016/j.fertnstert.2020.07.028 -
Molecular and Cellular Endocrinology Jun 2021The cervix undergoes extensive remodeling throughout pregnancy and parturition. This process involves both ECM collagen degradation and cellular remodeling, which...
The cervix undergoes extensive remodeling throughout pregnancy and parturition. This process involves both ECM collagen degradation and cellular remodeling, which includes cell proliferation, transition and migration. Progesterone (P4) has been used clinically to delay cervical ripening and prevent preterm birth (PTB). However, the mechanisms by which progesterone affects cell transition and the migration of cervical epithelial and stromal cells are not yet fully known. In this study, we documented the role of a gestational level of P4 in the cellular transition (epithelial-mesenchymal transition [EMT] and mesenchymal-epithelial transition [MET]), cell migration, and inflammatory responses of endocervical epithelial cells (EEC) and cervical stromal cells (CSC). EEC and CSC were treated with LPS and P4 for 6 days. The epithelial:mesenchymal ratio (regular microscopy and cell shape index analysis), shift in intermediate filaments (immunofluorescence microscopy and western blot analyses for cytokeratin [CK]-18 and vimentin), adhesion molecules and transcription factors (western blot analyses for E-cadherin, N-cadherin and SNAIL), were used to determine growth characteristics and EMT and MET changes in EEC and CSC under the indicated conditions. To test cell remodeling, scratch assays followed by cellular analyses as mentioned above were performed. Inflammatory cytokines (interleukin-6 [IL-6], tumor necrosis factor α [TNFα]) and matrix metallopeptidase 9 (MMP9) were measured by ELISA. LPS promoted EMT (decreased cell shape index, decreased CK-18 and E-cadherin, increased vimentin, N-cadherin, and SNAIL), and increased IL-6 and MMP9 production by EEC. A gestational level of P4 prevented LPS-induced EMT in EEC and exhibited anti-inflammatory effect in both EEC and CSC. LPS slowed down wound healing in CSC but P4 treatment prevented the negative impact of LPS in CSC wound healing. These results may explain the cellular mechanisms by which P4 helps to stabilize the cervical epithelial barrier and preserve the mechanical and tensile strength of the cervical stromal layer, which are important in normal cervical remodeling processes during pregnancy.
Topics: Antigens, CD; Cadherins; Cell Line, Transformed; Cell Movement; Cell Proliferation; Cervix Uteri; Epithelial Cells; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation; Humans; Interleukin-6; Keratin-18; Lipopolysaccharides; Matrix Metalloproteinase 9; Parturition; Pregnancy; Premature Birth; Progesterone; Signal Transduction; Snail Family Transcription Factors; Stromal Cells; Vimentin
PubMed: 33823217
DOI: 10.1016/j.mce.2021.111276 -
Breast Cancer Research : BCR Nov 2020Based on the androgen receptor (AR) expression, triple-negative breast cancer (TNBC) can be subdivided into AR-positive TNBC and AR-negative TNBC, also known as... (Review)
Review
Based on the androgen receptor (AR) expression, triple-negative breast cancer (TNBC) can be subdivided into AR-positive TNBC and AR-negative TNBC, also known as quadruple-negative breast cancer (QNBC). QNBC characterization and treatment is fraught with many challenges. In QNBC, there is a greater paucity of prognostic biomarkers and therapeutic targets than AR-positive TNBC. Although the prognostic role of AR in TNBC remains controversial, many studies revealed that a lack of AR expression confers a more aggressive disease course. Literature characterizing QNBC tumor biology and uncovering novel biomarkers for improved management of the disease remains scarce. In this comprehensive review, we summarize the current QNBC landscape and propose avenues for future research, suggesting potential biomarkers and therapeutic strategies that warrant investigation.
Topics: Antineoplastic Agents, Hormonal; Biomarkers, Tumor; Breast; Chemotherapy, Adjuvant; Clinical Trials as Topic; Disease-Free Survival; Gene Expression Regulation, Neoplastic; Humans; Mastectomy; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Prognosis; Receptor, ErbB-2; Receptors, Androgen; Receptors, Estrogen; Receptors, Progesterone; Triple Negative Breast Neoplasms
PubMed: 33213491
DOI: 10.1186/s13058-020-01369-5 -
Proceedings of the National Academy of... Dec 2020Effective cancer prevention requires the discovery and intervention of a factor critical to cancer development. Here we show that ovarian progesterone is a crucial...
Effective cancer prevention requires the discovery and intervention of a factor critical to cancer development. Here we show that ovarian progesterone is a crucial endogenous factor inducing the development of primary tumors progressing to metastatic ovarian cancer in a mouse model of high-grade serous carcinoma (HGSC), the most common and deadliest ovarian cancer type. Blocking progesterone signaling by the pharmacologic inhibitor mifepristone or by genetic deletion of the progesterone receptor (PR) effectively suppressed HGSC development and its peritoneal metastases. Strikingly, mifepristone treatment profoundly improved mouse survival (∼18 human years). Hence, targeting progesterone/PR signaling could offer an effective chemopreventive strategy, particularly in high-risk populations of women carrying a deleterious mutation in the gene.
Topics: Adult; Animals; BRCA1 Protein; Breast; Breast Neoplasms; Cystadenocarcinoma, Serous; Disease Models, Animal; Estradiol; Female; Humans; Mice; Middle Aged; Mifepristone; Mutation; Neoplasms, Experimental; Ovarian Neoplasms; Ovary; Progesterone; Receptors, Progesterone; Salpingo-oophorectomy; Signal Transduction
PubMed: 33262282
DOI: 10.1073/pnas.2013595117 -
Fertility and Sterility May 2022To investigate whether poor ovarian response in young patients undergoing in vitro fertilization simply involves lesser follicle growth due to diminished ovarian...
OBJECTIVE
To investigate whether poor ovarian response in young patients undergoing in vitro fertilization simply involves lesser follicle growth due to diminished ovarian reserve or whether there are intrinsic perturbations in the ovary.
DESIGN
A translational research study.
SETTING
University Hospital Translational Research Center.
PATIENT(S)
A total of 40 patients undergoing in vitro fertilization (20 normal and 20 poor responders) with ovarian stimulation using a gonadotropin-releasing hormone antagonist and recombinant follicle-stimulating hormone were included in the study.
INTERVENTION(S)
None.
MAIN OUTCOME MEASURE(S)
Luteal granulosa cells obtained during oocyte retrieval procedures were used for the experiments. Cell culture, quantitative real-time polymerase chain reaction, immunoblotting, confocal time-lapse live-cell imaging, and hormone assays were used.
RESULT(S)
We tracked the steroidogenic pathway starting from the very initial step of cholesterol uptake to the final step of estradiol and progesterone production in luteal granulosa cells and identified some previously unknown intrinsic defects in the poor responders. Most notably, the expression of low-density lipoprotein receptors was significantly down-regulated and the uptake of cholesterol and its cytoplasmic accumulation and transportation to mitochondria were substantially delayed and reduced in the poor responders. Further, the expression of the steroidogenic enzymes steroidogenic acute regulatory protein, 3β-hydroxysteroid dehydrogenase, and aromatase as well as gonadotropin receptors was defective, and the response of the cells to exogenous follicle-stimulating hormone and human chorionic gonadotropin was blunted, leading to compromised basal and gonadotropin-stimulated estradiol and progesterone production in the poor responders.
CONCLUSION(S)
This study demonstrates that poor ovarian response in young individuals should not simply be regarded as lesser follicle growth due to diminished ovarian reserve because the underlying pathogenetic mechanisms appear to be much more complex.
Topics: Chorionic Gonadotropin; Estradiol; Female; Fertilization in Vitro; Follicle Stimulating Hormone; Granulosa Cells; Humans; Luteal Cells; Ovulation Induction; Progesterone
PubMed: 35292154
DOI: 10.1016/j.fertnstert.2022.01.024 -
Pharmacology, Biochemistry, and Behavior Jul 2022Ovarian hormones influence the activity of endogenous opioids, and exogenous administration of estradiol reduces opioid intake and opioid seeking in animal models of...
Ovarian hormones influence the activity of endogenous opioids, and exogenous administration of estradiol reduces opioid intake and opioid seeking in animal models of opioid reward and reinforcement. The purpose of this study was to examine the effects of ovarian hormones on the discriminative stimulus effects of morphine and naloxone-precipitated opioid withdrawal. To this end, separate groups of ovariectomized female rats were trained to discriminate the stimulus effects of either 3.0 or 10 mg/kg morphine, and substitution tests were conducted with estradiol or progesterone alone and in combination with morphine. At the conclusion of discrimination testing, rats were treated chronically with estradiol, progesterone, or their combination, and challenged with naloxone to measure opioid-like withdrawal symptoms. Finally, the effects of estradiol, progesterone, and their combination were examined on naloxone-precipitated withdrawal in morphine-dependent rats. Neither estradiol nor progesterone substituted for the morphine discriminative stimulus, but estradiol significantly increased the potency of morphine in rats trained to discriminate 10 mg/kg but not 3 mg/kg morphine. When administered chronically, neither hormone nor their combination produced an opioid-like withdrawal syndrome following a naloxone challenge. Acute administration of estradiol, but not progesterone or a combination of estradiol and progesterone, significantly reduced naloxone-precipitated weight loss in morphine-dependent rats. These data indicate that estradiol influences the behavioral effects of morphine, possibly by increasing endogenous tone at mu opioid receptors.
Topics: Analgesics, Opioid; Animals; Estradiol; Female; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Progesterone; Rats; Receptors, Opioid, mu; Substance Withdrawal Syndrome; Substance-Related Disorders
PubMed: 35850178
DOI: 10.1016/j.pbb.2022.173431 -
The Cochrane Database of Systematic... Jul 2017Endometriosis is defined as the presence of endometrial tissue (glands and stroma) outside the uterine cavity. This condition is oestrogen-dependent and thus is seen... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Endometriosis is defined as the presence of endometrial tissue (glands and stroma) outside the uterine cavity. This condition is oestrogen-dependent and thus is seen primarily during the reproductive years. Owing to their antiproliferative effects in the endometrium, progesterone receptor modulators (PRMs) have been advocated for treatment of endometriosis.
OBJECTIVES
To assess the effectiveness and safety of PRMs primarily in terms of pain relief as compared with other treatments or placebo or no treatment in women of reproductive age with endometriosis.
SEARCH METHODS
We searched the following electronic databases, trial registers, and websites: the Cochrane Gynaecology and Fertility Group (CGFG) Specialised Register of Controlled Trials, the Central Register of Studies Online (CRSO), MEDLINE, Embase, PsycINFO, clinicaltrials.gov, and the World Health Organization (WHO) platform, from inception to 28 November 2016. We handsearched reference lists of articles retrieved by the search.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) published in all languages that examined effects of PRMs for treatment of symptomatic endometriosis.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures as expected by the Cochrane Collaboration. Primary outcomes included measures of pain and side effects.
MAIN RESULTS
We included 10 randomised controlled trials (RCTs) with 960 women. Two RCTs compared mifepristone versus placebo or versus a different dose of mifepristone, one RCT compared asoprisnil versus placebo, one compared ulipristal versus leuprolide acetate, and four compared gestrinone versus danazol, gonadotropin-releasing hormone (GnRH) analogues, or a different dose of gestrinone. The quality of evidence ranged from high to very low. The main limitations were serious risk of bias (associated with poor reporting of methods and high or unclear rates of attrition in most studies), very serious imprecision (associated with low event rates and wide confidence intervals), and indirectness (outcome assessed in a select subgroup of participants). Mifepristone versus placebo One study made this comparison and reported rates of painful symptoms among women who reported symptoms at baseline.At three months, the mifepristone group had lower rates of dysmenorrhoea (odds ratio (OR) 0.08, 95% confidence interval (CI) 0.04 to 0.17; one RCT, n =352; moderate-quality evidence), suggesting that if 40% of women taking placebo experience dysmenorrhoea, then between 3% and 10% of women taking mifepristone will do so. The mifepristone group also had lower rates of dyspareunia (OR 0.23, 95% CI 0.11 to 0.51; one RCT, n = 223; low-quality evidence). However, the mifepristone group had higher rates of side effects: Nearly 90% had amenorrhoea and 24% had hot flushes, although the placebo group reported only one event of each (1%) (high-quality evidence). Evidence was insufficient to show differences in rates of nausea, vomiting, or fatigue, if present. Mifepristone dose comparisons Two studies compared doses of mifepristone and found insufficient evidence to show differences between different doses in terms of effectiveness or safety, if present. However, subgroup analysis of comparisons between mifepristone and placebo suggest that the 2.5 mg dose may be less effective than 5 mg or 10 mg for treating dysmenorrhoea or dyspareunia. Gestrinone comparisons Ons study compared gestrinone with danazol, and another study compared gestrinone with leuprolin.Evidence was insufficient to show differences, if present, between gestrinone and danazol in rate of pain relief (those reporting no or mild pelvic pain) (OR 0.71, 95% CI 0.33 to 1.56; two RCTs, n = 230; very low-quality evidence), dysmenorrhoea (OR 0.72, 95% CI 0.39 to 1.33; two RCTs, n = 214; very low-quality evidence), or dyspareunia (OR 0.83, 95% CI 0.37 to 1.86; two RCTs, n = 222; very low-quality evidence). The gestrinone group had a higher rate of hirsutism (OR 2.63, 95% CI 1.60 to 4.32; two RCTs, n = 302; very low-quality evidence) and a lower rate of decreased breast size (OR 0.62, 95% CI 0.38 to 0.98; two RCTs, n = 302; low-quality evidence). Evidence was insufficient to show differences between groups, if present, in rate of hot flushes (OR 0.79, 95% CI 0.50 to 1.26; two RCTs, n = 302; very low-quality evidence) or acne (OR 1.45, 95% CI 0.90 to 2.33; two RCTs, n = 302; low-quality evidence).When researchers compared gestrinone versus leuprolin through measurements on the 1 to 3 verbal rating scale (lower score denotes benefit), the mean dysmenorrhoea score was higher in the gestrinone group (MD 0.35 points, 95% CI 0.12 to 0.58; one RCT, n = 55; low-quality evidence), but the mean dyspareunia score was lower in this group (MD 0.33 points, 95% CI 0.62 to 0.04; low-quality evidence). The gestrinone group had lower rates of amenorrhoea (OR 0.04, 95% CI 0.01 to 0.38; one RCT, n = 49; low-quality evidence) and hot flushes (OR 0.20, 95% CI 0.06 to 0.63; one study, n = 55; low quality evidence) but higher rates of spotting or bleeding (OR 22.92, 95% CI 2.64 to 198.66; one RCT, n = 49; low-quality evidence).Evidence was insufficient to show differences in effectiveness or safety between different doses of gestrinone, if present. Asoprisnil versus placebo One study (n = 130) made this comparison but did not report data suitable for analysis. Ulipristal versus leuprolide acetate One study (n = 38) made this comparison but did not report data suitable for analysis.
AUTHORS' CONCLUSIONS
Among women with endometriosis, moderate-quality evidence shows that mifepristone relieves dysmenorrhoea, and low-quality evidence suggests that this agent relieves dyspareunia, although amenorrhoea and hot flushes are common side effects. Data on dosage were inconclusive, although they suggest that the 2.5 mg dose of mifepristone may be less effective than higher doses. We found insufficient evidence to permit firm conclusions about the safety and effectiveness of other progesterone receptor modulators.
Topics: Danazol; Dysmenorrhea; Dyspareunia; Endometriosis; Estrenes; Female; Gestrinone; Gonadotropin-Releasing Hormone; Hormone Antagonists; Humans; Leuprolide; Mifepristone; Norpregnadienes; Oximes; Prevalence; Randomized Controlled Trials as Topic; Receptors, Progesterone
PubMed: 28742263
DOI: 10.1002/14651858.CD009881.pub2