Androgen receptor polyglutamine tract length in Egyptian male breast cancer patients

Abstract

Male Breast Cancer (MBC) is a rare disease in the U.S., accounting for less than 1% of all breast cancers. Rates of MBC in Africa are more variable than in the U.S., therefore, understanding the risk factors involved in a population like Egypt can clarify the nature of MBC. The polyglutamine tract (QT) is a variable region of the androgen receptor (AR), a nuclear receptor which is important in modulating androgen actions and generally inhibits growth in breast tissue. It is hypothesized that a long QT results in weaker AR activity over the lifetime, resulting in less AR mediated control over cellular division and higher risk of MBC. As a corollary, we expect to see a distribution skewed toward longer QTs in MBC patients compared to controls and overall relatively longer QT’s in populations with higher rates of MBC. This study aimed to investigate for the first time the distribution of AR QT lengths among MBC patients in Egypt. Paraffin-embedded tumor tissues from 44 Egyptian MBC patients were analyzed for this polymorphism. Amplification followed by fragment length analysis revealed QT length. For the control series, blood from 43 Egyptian males without a family or personal history of breast or prostate cancers was collected and analyzed similarly. There was no significant difference between patients and controls with respect to mean QT length (P = 0.84; means were 19.5 ± 2.8 and 19.3 ± 4.2, for patients and controls, respectively). Though, short QT lengths were more prevalent among controls (14.0%), but almost absent in cases (2.3%). Although the mean lengths were not different in cases and controls, the near absence of short tracts in cases suggests a possible protective effect of very short QT lengths against MBC. In populations in which there is variable incidence of MBC by region, investigations of the distribution of AR QT lengths are warranted to further delineate its role as a risk factor in MBC.

Androgen receptor and antiandrogen therapy in male breast cancer

“…Two studies searching for an association between CAG repeat length and MBC did not notice any appreciable differences between cases and the respective control groups [22,25]. Two other studies suggested that longer CAG repeats are more common in MBC that in controls [26,27], and a trend toward a higher frequency of shorter CAG tracts in the control group emerged from a fifth report [28]. Thus, even though genetic evidence is scarce and somewhat ambiguous, the scenario proposed is that androgen hyposensitivity caused by either AR mutations or long CAG repeats might be a causal factor for MBC.…”

Clinical profile, BRCA2 expression, and the androgen receptor CAG repeat region in Egyptian and Moroccan male breast cancer patients

“…CAG repeat length data on the Moroccan patients were not available because of the limited amount of tissues available for this study. However, in previous studies, it has been seen that short CAG repeat lengths are more prevalent among non-MBC controls compared to MBC patients [20,48]. It should also be noted that our study’s finding of CAG repeat lengths of Egyptian MBC patients (19.5 ± 2.8) and controls (19.3 ± 4.2) are in agreement with a previous study that found an average CAG repeat length of 18.18 ± 3.63 for healthy Egyptian men [2].…”

“…PCR amplification of isolated patient DNA followed by fragment length analysis according to the methods described by Gilbert et al, 2011, reveal the number of CAG repeats in this region. A case-control study comparing the CAG repeat lengths in the 44 Egyptian MBC tumor and 43 non-MBC controls found no significant difference in amount of repeats (MBC cases: 19.5 ± 2.8 repeats, Controls: 19.3 ± 4.2 repeats, P = 0.843), but did note a higher proportion of short repeat lengths among controls, possibly suggesting a protective effect of short CAG repeat lengths [20]. A similar case-control study of the androgen receptor CAG repeat length was not done with the Moroccan samples due to the limited amount of tissues available.…”

“…A longer CAG repeat length would then result in a longer and weaker AR, which may be a predisposition for breast cancer. Our recent study on Egyptian MBC showed no significant difference in the CAG repeat length between MBC patients and healthy men [20]. This study aimed to describe and compare the clinical and selected molecular features, including BRCA2 expression, of MBC patients in Egypt and Morocco from 1999-2006 to explain the different incident rates in the two countries.…”

Long CAG Repeat Sequence and Protein Expression of Androgen Receptor Considered as Prognostic Indicators in Male Breast Carcinoma

“…100 ng of DNA was amplified in a reaction mix containing 1 µl of each primer at 10 pmol, 0.8 µl 50 mM MgCl 2 , 0.2 µl Platinum® Taq DNA polymerase (Life technologies Invitrogen, USA), 10 µl of Gene Amp Fast PCR Mix from ABI (Applied Biosystems, USA), and distilled water to bring to final volume to 25 µl. PCR was performed according to a standard protocol (modified from Gilbert SF [6]); starting with 94°C for 2 min; followed by 30 cycles of 94°C denaturation for 30 s, 55°C annealing for 30 s, and 72°C extension for 1 min; ending with a final extension at 72°C for 30 min. Digital images of fluorescent gel data were acquired using Data Collection Software and analyzed using GeneScan Software (both from Applied Biosystems).…”