Androgen Receptor Index Research Articles

Evaluating Biomarker Dynamics in Breast Cancer Post-Neoadjuvant Chemotherapy: A Retrospective Cross-sectional Study

Background: Neoadjuvant chemotherapy (NACT) is integral to breast cancer management, yet its influence on biomarkers, notably androgen receptor (AR), remains underexplored. This study examines post-NACT alterations in receptor status, including ER, PR AR, HER2 and Ki67 index in breast cancer patients. Methods: A cross-sectional study, spanning three years at a tertiary care center, enrolled patients with invasive breast cancer undergoing mastectomy post-NACT. Pre- and post-NACT specimens underwent histological grading and immunohistochemistry for hormone status, HER2 status, and Ki67 index. Discordance between pre- and post-NACT receptor statuses and expression levels of biomarkers was assessed using McNemar’s and Wilcoxon signed rank tests respectively. Results: Among 100 patients, 35 were assessed. Mean age was 43.83 years, with prevalent T1 tumors (34.3%) and N1 nodal involvement (37.1%). Post-NACT, 54.2% showed no histological grade change. Notable alterations included changes in ER (14.2%), PR (14.2%), and HER2 status (8.57%). AR expression showed a significant change following NACT (p=0.03), while ER expression exhibited a trend towards significance (p=0.06). Ki67 index decreased in only 5.7% of cases. Conclusion: This study unveils intricate biomarker dynamics following NACT in breast cancer, with particular emphasis on AR, hitherto not evaluated. Larger investigations are imperative to elucidate clinical implications and tailor treatment strategies for breast cancer patients undergoing NACT.

Cell-by-cell quantification of the androgen receptor in benign and malignant prostate leads to a better understanding of changes linked to cancer initiation and progression.

The androgen receptor (AR) plays a crucial role in the development and homeostasis of the prostate and is a key therapeutic target in prostate cancer (PCa). The gold standard therapy for advanced PCa is androgen deprivation therapy (ADT), which targets androgen production and AR signaling. However, resistance to ADT develops via AR-dependent and AR-independent mechanisms. As reports on AR expression patterns in PCa have been conflicting, we performed cell-by-cell AR quantification by immunohistochemistry in the benign and malignant prostate to monitor changes with disease development, progression, and hormonal treatment. Prostates from radical prostatectomy (RP) cases, both hormone-naïve and hormone-treated, prostate tissues from patients on palliative ADT, and bone metastases were included. In the normal prostate, AR is expressed in >99% of luminal cells, 51% of basal cells, and 61% of fibroblasts. An increase in the percentage of AR negative (%AR-) cancer cells along with a gradual loss of fibroblastic AR were observed with increasing Gleason grade and hormonal treatment. This was accompanied by a parallel increase in staining intensity of AR positive (AR+) cells under ADT. Staining AR with N- and C-terminal antibodies yielded similar results. The combination of %AR- cancer cells, %AR- fibroblasts, and AR intensity score led to the definition of an AR index, which was predictive of biochemical recurrence in the RP cohort and further stratified patients of intermediate risk. Lastly, androgen receptor variant 7 (ARV7)+ cells and AR- cells expressing neuroendocrine and stem markers were interspersed among a majority of AR+ cells in ADT cases. Altogether, the comprehensive quantification of AR expression in the prostate reveals concomitant changes in tumor cell subtypes and fibroblasts, emphasizing the significance of AR- cells with disease progression and palliative ADT.

Androgen Receptor Expression in Triple Negative Breast Cancer - Study from a Tertiary Health Care Center in South India

Abstract Background: The treatment of breast cancer is based on a multi-modality approach. Analysis of the hormone receptor has been accepted as a standard procedure, in the routine management of breast cancer patients. Triple negative breast cancers (TNBCs) are those which are negative for expression of all three markers, i.e., estrogen receptor, progesterone receptor (PR), and human epidermal growth factor receptor. High expression of Ki-67, a proliferation index, has been associated with a worse prognosis in TNBC. TN cancers are aggressive in nature as they do not respond to routine targeted therapy. The role of the androgen receptor (AR) in breast carcinomas is important as AR has been suggested as a potential therapeutic target. We did this study to assess AR immunoreactivity in TNBCs and correlate with Ki-67 index. Materials and Methods: In this study group, there were 45 cases of TN invasive breast carcinomas. These tumors were analyzed with respect to AR and Ki-67 index. Results: Of 45 TN breast carcinomas analyzed, 42 were infiltrating duct cell carcinoma (IDCC) of not otherwise specified type. There were one medullary and two metaplastic carcinomas. The median age was 46 years. AR was positive in 20% (9/45) of cases. All the AR positive cases were an IDCC (nos). Out of the nine AR positive cases, six showed positivity for Ki-67. The statistical analysis using Pearson's Chi-squared method did not reveal any correlation between AR and Ki-67 index (P = 0.574). Conclusion: Although our study did not reveal any statistically significant correlation between AR and Ki-67 index, assessment of AR status in TNBC patients is desirable as it may help to develop a targeted therapy in future in these aggressive cancers.

The increased expression of fatty acid-binding protein 9 in prostate cancer and its prognostic significance.

In contrast to numerous studies conducted to investigate the crucial role of fatty acid binding protein 5 (FABP5) in prostate cancer, investigations on the possible involvement of other FABPs are rare. Here we first measured the mRNA levels of 10 FABPs in benign and malignant prostate cell lines and identified the differentially expressed FABP6 and FABP9 mRNAs whose levels in all malignant cell lines were higher than those in the benign cells. Thereafter we assessed the expression status of FABP6 and FABP9 in both prostate cell lines and in human tissues. FABP6 protein was overexpressed only in 1 of the 5 malignant cell lines and its immunostaining intensities were not significantly different between benign and malignant prostate tissues. In contrast, FABP9 protein was highly expressed in highly malignant cell lines PC-3 and PC3-M, but its level in the benign PNT-2 and other malignant cell lines was not detectable. When analysed in an archival set of human prostate tissues, immunohistochemical staining intensity for FABP9 was significantly higher in carcinomas than in benign cases and the increase in FABP9 was significantly correlated with reduced patient survival times. Moreover, the increased level of staining for FABP9 was significantly associated with the increased joint Gleason scores (GS) and androgen receptor index (AR). Suppression of FABP9 expression in highly malignant PC3-M cells inhibited their invasive potential. Our results suggest that FABP9 is a valuable prognostic marker to predict the outcomes of prostate cancer patients, perhaps by playing an important role in prostate cancer cell invasion.

In Vivo Evidence of the Androgen Receptor in Association With Myometrial Cell Proliferation and Apoptosis.

The androgen receptor (AR) plays essential roles in female reproductive physiology. In vitro studies have shown that AR exerts 2 distinct but related functions in myometrial cells. The AR is required for myometrial cell cycling ligand independently, thereby controls myometrial cell proliferation. The AR also exerts antiapoptotic functions through myeloid cell leukemia 1 (MCL1) in both ligand-dependent and ligand-independent manners. However, these AR functions have not yet been confirmed in vivo. This study provides in vivo evidence that AR expression is associated with myometrial cell proliferation and apoptosis. Myometrial tissue was collected on day 6 of pregnancy from mice bearing an intact AR (AR+/+) or mice with AR heterozygous (AR-/+) or homozygous (AR-/-) functional knockout. Human uterine leiomyoma and paired myometrial tissue biopsies (n = 14 patients) were collected during hysterectomy. Immunohistochemistry was used to assess the protein expression of AR, MCL1, and Ki-67 index, as well as the functional associations of AR with MCL1 and Ki-67 index. In AR-/- mice, MCL1 protein levels were reduced ∼50% in both circular and longitudinal myometrial cells when compared with that in AR+/+ and AR-/+ mice. By contrast, Ki-67 index remained unchanged. The AR protein expression and Ki-67 index in leiomyoma were ∼2- to 3-fold higher than that in normal myometrium. Although MCL1 expression was not coordinately increased in leiomyoma, strong positive correlations between AR and MCL1 expression were observed in leiomyoma but not in normal myometrium tissue. These results suggest that AR is an important regulator of myometrial growth in vivo during pregnancy and in leiomyoma.

Epidermal androgen receptors in acne vulgaris patients before and following oral isotretinoin

IntroductionThe role of androgens and androgen receptors (AR) in the pathophysiology of acne vulgaris appears to be a complex phenomenon. It has been suggested earlier that oral administration of isotretinoin, the drug of choice for severe cases of acne, exerts its action through ARs, which is quite debatable. The aim is to study the response of androgen receptor (AR) in the skin of acne vulgaris patients by administrating isotretinoin orally. MethodsSkin biopsy was procured from untreated patients of severe cases of acne vulgaris. Out of these, twenty histopathologically confirmed patients were included in the study. They were treated with oral isotretinoin in the dose of 0.5 mg/kg/day for 12 weeks, following which their skin biopsies were repeated. Immunostaining for androgen receptor was performed using mouse monoclonal antibodies. Androgen receptor index (AR index) was calculated for the acne patients before and following treatment with oral isotretinoin. Statistical analysis was done using paired t-test. ResultThe AR indices in skin of untreated acne patients were higher in male patients (26.62 ± 20.74) as compared to the female patients (7.5 ± 10.61). AR indices after 12 weeks of oral isotretinoin treatment showed a reduction in both males and female patients (20.55 ± 16 and 4.71 ± 6.75 respectively). However, the post treatment reduction in AR index was statistically significant in male patients only. DiscussionDetermination of AR status can be helpful in planning the treatment methodology of severe cases of acne. Our study also implicates the effectiveness of oral isotretinoin on acne patients through its interaction with androgen receptor.

Androgen receptor and enzymes in lymph node metastasis and cancer reoccurrence in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptor, progesterone receptor and HER2. TNBCs are a diverse subgroup, but one promising marker and therapeutic target of this breast cancer is the androgen receptor (AR). Previously we demonstrated that AR and cognate intracrine pathways are associated with decreased proliferation in invasive ductal carcinoma with their decrease also detected between organ-confined and invasive diseases. Therefore, in this study, we examined the status of AR and androgen-producing enzymes during the process of metastasis to lymph nodes and cancer recurrence. We studied 2 series of patients with TNBC, one from Kumamoto University Hospital composed of 16 matched cases of primary and locally or distal recurrences and the other from Tohoku University Hospital examining 46 lymph node metastasis from 23 patients. In addition to studying concordance in AR expression, we also examined the interactions between AR and Ki-67 labeling index and AR and site of distal metastasis. In both series, AR status was concordant between primary and recurrent/metastatic disease, but coordinated expression of AR and androgenic enzymes was lost during the process. The inverse association between AR and Ki-67, previously reported in invasive ductal carcinoma (IDC), was markedly potentiated in both lymph node and recurrent cancers. In addition, AR expression appeared to have little effect on visceral metastasis but was associated directly with bone metastasis and inversely with brain metastasis. The results of our present study demonstrated that AR remained in the majority of metastatic samples from AR-positive primary TNBCs and that AR manipulation could be exploited in the metastatic settings of TNBC.

Expression of testicular androgen receptor in non-obstructive azoospermia and its change after hormonal therapy.

Several trials aimed at improving the sperm retrieval from men with non-obstructive azoospermia (NOA) by optimizing intratesticular testosterone (ITT) have reported partial responses, however, an appropriate level of ITT has not been identified. In this study, we examined the expression of the testicular androgen receptor (AR) in NOA and investigated its correlation with clinical and pathological parameters. Expression of the testicular AR was investigated in 52 men with NOA and 22 men with obstructive azoospermia (OA). Twenty-two patients for whom sperm retrieval failed during microdissection testicular sperm extraction (micro-TESE) were enrolled in hormonal therapy using hCG with or without recombinant human follicle stimulating hormone (rhFSH) prior to a second micro-TESE. Sertoli cells were identified by vimentin immunostaining, and positivity in Sertoli cells was used as the AR index. AR immunostaining was robust in the nuclei of Sertoli cells [Sertoli cell androgen receptor (SCAR)] in both OA and NOA. The mean AR index in NOA was significantly higher than that in OA (p < 0.05). In NOA patients, there was no correlation between the AR index and the clinical parameters, whereas the AR index of early maturation arrest (MA) was significantly lower than that of Sertoli cell only, late MA and hypospermatogenesis (p < 0.05). A significant increase in the AR index after salvage hormonal therapy was shown, particularly when using rhFSH. The AR index in patients from whom spermatozoa could be retrieved at the second micro-TESE increased significantly after hormonal therapy. In human testes, the expression of AR is dominant in Sertoli cells, and the expression of SCAR is upregulated by FSH. Germ cell maturation, especially during spermatogonia to spermatocyte stage, has been shown to be SCAR-dependent. Taken together, the results indicate that SCAR elevation is closely associated with sperm retrieval after hormonal therapy and that FSH-based hormonal therapy is potentially effective in NOA men with MA.

Androgen Receptor Levels of Oral and Genital Ulcers and Skin Pathergy Test in Patients with Behçet’s Disease

Background: Hormonal factors have long been proposed to play a role in Behçet’s disease (BD). Male sex, systemic onset, HLA-B51 positivity and a younger age of onset in BD are associated with severer disease, and the disease generally runs a milder course in women. Vascular involvement is more common, and the skin pathergy test (SPT) is more strongly positive in men. BD rarely develops before puberty or after the age of 50 years. Clinical manifestations of the disease, with the exception of eye symptoms, tend to improve with time. Therefore, BD may be androgen driven to some degree. Objectives: We aimed to investigate androgen receptor (AR) levels of oral ulcers (OU), genital ulcers (GU) and SPT areas and compared them with those of adjacent normal-appearing skin/mucosa from patients with BD. Methods: Thirty-eight patients with BD (16 female, 22 male; mean ± SD age, 36.45 ± 10.2 years), diagnosed according to the criteria of the International Study Group for Behçet’s Disease, were included in the study with blind histological examination. Biopsies from OU of 10 patients, GU of 11 patients, SPT areas of 17 patients and adjacent (approximately 2 cm distant) normal-appearing skin/mucosa in patients with BD were performed. Nuclear AR levels were studied by an immunohistochemical technique, using monoclonal antibodies. The percentage of positively staining cells was recorded as the AR index (ARI). In addition, the prevalence and the positivity rate of SPT has also been evaluated. Results: ARI values in the lesional and control (non-lesional adjacent) skin/mucosa were found to be 14.5 versus 18% for OU, 28.7 versus 25.5% for GU and 36.3 versus 21.8% (p = 0.068) for SPT areas. The positive SPT areas in male patients showed a higher ARI than those of female patients (43.36 and 23.33%; p = 0.078). The ARI values of SPT areas in male patients but not in female patients were found to be significantly higher as compared with non-lesional skin (21.63%; p = 0.039). The SPT positivity was also more common in male patients compared with female patients (86.4% and 62.5%), although the difference was not significant (p = 0.88). SPT have been found to be more strongly positive among the males (4.63 ± 3.3) compared with female patients (3.18 ± 1.9), and the difference was statistically significant (p = 0.022). Conclusions: Our findings indicate that androgens seem to play a role both in the formation and increased positivity of the SPT areas in male patients with BD.