In total, 40 relevant original articles (Glenn et al. 2012; Axel et al. 1972; Oskouee et al. 2014; Lawson et al. 2006, 2010, 2004; Bindra et al. 2007; Morales-Sanchez et al. 2013; Motamedifar et al. 2012; Park et al. 2011; Tabriz et al. 2013; Witt et al. 2003; Al Dossary et al. 2018; Cedro-Tanda et al. 2014; Etkind et al. 2000; Faedo et al. 2004; Ford et al. 2004, 2003; Hachana et al. 2008; Hafez et al. 2013; Levine et al. 1984; Luo et al. 2006; Mazzanti et al. 2011; Melana et al. 2002, 2001; Mok et al. 2008; Naccarato et al. 2019; Nartey et al. 2017; Naushad et al. 2014, 2017a, b); Pogo et al. 1999, 2010; Reza et al. 2015; San et al. 2017; Shariatpanahi et al. 2017; Slaoui et al. 2014; Wang et al. 1995; Zammarchi et al. 2006; Zapata-Benavides et al. 2007) (Table 1) were found on PubMed which investigated the association of MMTV-like virus with BC in 24 different populations. Table 1 enlists all these articles with summarized information extracted from these articles including information about the studied population, technique used for the detection of MMTV-like virus, target gene, number (No) of screened samples (normal, adjacent/benign, and BC) with their respective identified population-wise positivity ratios. Out of all the 40 studies, in total, 23 studies (Glenn et al. 2012; Oskouee et al. 2014; Bindra et al. 2007; Morales-Sanchez et al. 2013; Motamedifar et al. 2012; Al Dossary et al. 2018; Cedro-Tanda et al. 2014; Etkind et al. 2000; Ford et al. 2004, 2003; Hafez et al. 2013; Lawson et al. 2010; Levine et al. 1984; Mazzanti et al. 2011; Melana et al. 2002, 2001; Nartey et al. 2017; Naushad et al. 2014; Pogo et al. 2010; Reza et al. 2015; Shariatpanahi et al. 2017; Slaoui et al. 2014; Wang et al. 1995) were the case–control studies in which normal, adjacent/benign, and BC samples were screened, while others were not.
The positivity ratio of MMTV-like virus detection in BC samples was varied population-wise from 0% (Oskouee et al. 2014; Bindra et al. 2007; Morales-Sanchez et al. 2013; Motamedifar et al. 2012; Park et al. 2011; Tabriz et al. 2013; Witt et al. 2003) to 78.9% (Axel et al. 1972) in all the 40 identified studies, while the positivity ratio of MMTV-like virus detection in normal and adjacent/benign controls was varied from 0% (Oskouee et al. 2014; Motamedifar et al. 2012; Al Dossary et al. 2018; Etkind et al. 2000; Ford et al. 2003; Lawson et al. 2010; Mazzanti et al. 2011; Naushad et al. 2014; Reza et al. 2015) to 32% (Glenn et al. 2012) and 0% (Bindra et al. 2007; Levine et al. 1984; Melana et al. 2002) to 33.3% (Slaoui et al. 2014), respectively.
The results obtained after careful evaluation of the extracted data through the Bradford Hill criteria postulates showed that all the identified studies from various populations do not fulfill the major postulates including temporality, consistency, biological gradient, experiment, coherence, specificity, and analogy. Hence, no causal relationship has been suggested between MMTV-like virus and BC patients of any included population.
Polymerase chain reaction (PCR) technique was employed by most of the studies (Glenn et al. 2012; Oskouee et al. 2014; Lawson et al. 2006, 2010, 2004; Bindra et al. 2007; Morales-Sanchez et al. 2013; Motamedifar et al. 2012; Park et al. 2011; Tabriz et al. 2013; Witt et al. 2003; Al Dossary et al. 2018; Cedro-Tanda et al. 2014; Etkind et al. 2000; Faedo et al. 2004; Ford et al. 2004, 2003; Hachana et al. 2008; Hafez et al. 2013; Luo et al. 2006; Mazzanti et al. 2011; Melana et al. 2002, 2001; Mok et al. 2008; Naccarato et al. 2019; Nartey et al. 2017; Naushad et al. 2014, 2017a, b; Pogo et al. 1999, 2010; Reza et al. 2015; San et al. 2017; Shariatpanahi et al. 2017; Slaoui et al. 2014; Wang et al. 1995; Zammarchi et al. 2006; Zapata-Benavides et al. 2007) to detect the presence of MMTV-like virus in the normal, adjacent/benign and BC samples using Env (Glenn et al. 2012; Oskouee et al. 2014; Lawson et al. 2006, 2010, 2004; Bindra et al. 2007; Morales-Sanchez et al. 2013; Motamedifar et al. 2012; Park et al. 2011; Tabriz et al. 2013; Witt et al. 2003; Al Dossary et al. 2018; Cedro-Tanda et al. 2014; Etkind et al. 2000; Faedo et al. 2004; Ford et al. 2004, 2003; Hachana et al. 2008; Hafez et al. 2013; Luo et al. 2006; Mazzanti et al. 2011; Melana et al. 2001; Mok et al. 2008; Naccarato et al. 2019; Nartey et al. 2017; Naushad et al. 2014, 2017a, b; Pogo et al. 1999, 2010; Reza et al. 2015; San et al. 2017; Shariatpanahi et al. 2017; Slaoui et al. 2014; Wang et al. 1995; Zammarchi et al. 2006; Zapata-Benavides et al. 2007), Ltr (Naushad et al. 2014, 2017a, b), and gp52 (Lawson et al. 2010; Levine et al. 1984) gene-specific primers. Additionally, from them, few studies (Glenn et al. 2012; Bindra et al. 2007; Morales-Sanchez et al. 2013; Al Dossary et al. 2018; Cedro-Tanda et al. 2014; Etkind et al. 2000; Ford et al. 2004, 2003; Lawson et al. 2010; Mazzanti et al. 2011; Melana et al. 2001; Mok et al. 2008; Naccarato et al. 2019; Nartey et al. 2017; Naushad et al. 2017; San et al. 2017; Slaoui et al. 2014; Zammarchi et al. 2006; Zapata-Benavides et al. 2007) also employed the second techniques for validating their PCR positive results using second techniques such as immunohistochemistry (Lawson et al. 2010; Naccarato et al. 2019), in situ hybridization (Mazzanti et al. 2011), real-time PCR (Mazzanti et al. 2011), and DNA sequencing analysis (Glenn et al. 2012; Bindra et al. 2007; Morales-Sanchez et al. 2013; Al Dossary et al. 2018; Cedro-Tanda et al. 2014; Etkind et al. 2000; Ford et al. 2004, 2003; Melana et al. 2001; Mok et al. 2008; Nartey et al. 2017; Naushad et al. 2017; San et al. 2017; Slaoui et al. 2014; Zammarchi et al. 2006; Zapata-Benavides et al. 2007). On the other hand, few studies also utilized antigen detection method (Levine et al. 1984) and molecular hybridization method (Axel et al. 1972) for the detection of MMTV-like virus.
Further details regarding population-specific MMTV-like virus etiology in BC have been given as follows:
In Australia, a total of 09 studies (Glenn et al. 2012; Lawson et al. 2006, 2010, 2004; Park et al. 2011; Faedo et al. 2004; Ford et al. 2004; Mok et al. 2008; Nartey et al. 2017) including 4 case–control studies (Glenn et al. 2012; Ford et al. 2004; Lawson et al. 2010; Nartey et al. 2017) have been reported so far to demonstrate MMTV-like virus etiology in BC. These studies used PCR technique with the help of Env gene-specific primers for MMTV-LIKE VIRUS detection and documented differential MMTV-like virus detection positivity ratios varying between 0% (Park et al. 2011) and 78.9% (Axel et al. 1972) in BC samples, while 20% (Ford et al. 2004) to 24% (Nartey et al. 2017) in adjacent/benign samples and 0% (Lawson et al. 2010) to 32% (Glenn et al. 2012) in normal controls.
In Pakistan, the association between MMTV-like virus and BC has been reported in only 03 studies (Naushad et al. 2014, 2017a, b) so far. They utilized PCR technique with primers specifically targeting the Env and LTR regions of the viral genome and documented varying MMTV-like virus detection positivity ratio ranging from 11.6% (Naushad et al. 2017) to 46.25% (Naushad et al. 2014) in BC samples.
A total of 05 studies (Oskouee et al. 2014; Motamedifar et al. 2012; Tabriz et al. 2013; Reza et al. 2015; Shariatpanahi et al. 2017) including 04 case–control studies (Oskouee et al. 2014; Motamedifar et al. 2012; Reza et al. 2015; Shariatpanahi et al. 2017) have been carried out in Iran so far, analyzing the association between MMTV-like virus and BC. These studies utilized PCR technique with primers specific for the Env region of the viral genome and documented varying MMTV-like virus detection positivity ratios ranging from 0% (Oskouee et al. 2014; Motamedifar et al. 2012; Tabriz et al. 2013) to 32.2% (Shariatpanahi et al. 2017) in BC samples, while 0% (Oskouee et al. 2014; Motamedifar et al. 2012; Reza et al. 2015) and 5% (Shariatpanahi et al. 2017) in the normal and adjacent/benign controls, respectively.
A single case–control study (Slaoui et al. 2014) has been conducted in Morocco so far to determine the association between MMTV-like virus and BC. They analyzed 42 BC samples and 18 adjacent/benign controls for the identification of MMTV-like virus in BC using PCR technique with primers specifically hybridizing in the Env sequence of the viral genome. They documented 57.1% and 33.3% MMTV-like virus detection positivity ratios in BC and adjacent/benign controls, respectively.
In Austria, only a single study (Witt et al. 2003) has been reported to date to relating MMTV-like virus presence with BC. They screened 50 BC samples using PCR technique with primers specifically targeting the Env sequence of the viral genome and they documented 0% MMTV-like virus detection positivity ratio in BC samples.
Until now, only a single case–control study (Hafez et al. 2013) has been carried out in Egypt to find out the etiological association between MMTV-like virus and BC. They analyzed 100 BC samples and 50 adjacent/benign controls using PCR technique with Env gene-specific primers for MMTV-like virus detection. They reported the higher MMTV-like virus detection positivity ratio in BC samples (36%) as compared to the adjacent/benign controls (4%).
In Vietnam, there has been a single case–control study (Ford et al. 2003) reported so far to find out if MMTV-like virus has any association with BC. They utilized PCR technique with primers specifically targeting the Env sequence of the viral genome and documented a 0.83% MMTV-like virus detection positivity ratio in BC samples and normal controls, respectively.
Until now, only a single case–control study (Melana et al. 2002) has been carried out in Argentina to elaborate the role of MMTV-like virus in the development of BC. They screened 74 BC samples paired with adjacent/benign controls using PCR technique with primers targeting the envelope sequence of the viral genome. They documented the higher MMTV-like virus detection positivity ratios in BC samples (31%) as compared to the adjacent/benign samples (0%) and normal controls (1.35%).
In Sweden, a single case–control (Bindra et al. 2007) has been carried out so far to identify the casual relationship between MMTV-like virus and BC using RT-PCR technique and they did not detect MMTV-like virus in any of the BC or control sample.
So far, a single case–control study (Al Dossary et al. 2018) has been carried out in Saudi Arabia to find out the association between MMTV-like virus and BC. They screened a total of 101 BC, 51 normal, and 93 adjacent/benign controls using PCR technique with primers specific for the Env region of the viral genome and documented MMTV-like virus positivity ratios was higher in the adjacent/benign controls (9.7%) as compared to the normal (0%) and BC samples (5.9%).
In Tunisia, a total of 03 studies (Hachana et al. 2008; Levine et al. 1984; Pogo et al. 2010) including 02 case–control studies (Levine et al. 1984; Pogo et al. 2010) have been reported so far to find out whether MMTV-like virus have any association with BC. They utilized antigen detection method and PCR technique with Env gene-specific primers for MMTV-like virus detection and documented MMTV-like virus detection positivity ratios with varying frequencies ranging from 3.9% (Hachana et al. 2008) to 73.7% (Pogo et al. 2010) in BC samples, while 0% (Levine et al. 1984) and 1.4% (Pogo et al. 2010) in adjacent/benign and normal samples, respectively.
To date, a total of 04 studies (Axel et al. 1972; Etkind et al. 2000; Pogo et al. 2010; Wang et al. 1995) including 3 case–control studies (Etkind et al. 2000; Pogo et al. 2010; Wang et al. 1995) have been carried out in the USA to elaborate the causal association between in adjacent/benign samples and BC. All these studies employed PCR technique with Env gene-specific primers and documented MMTV-like virus detection positivity ratios ranging from 36.9% (Etkind et al. 2000) to 45.5% (Pogo et al. 2010) in BC samples, while 6.9% (Wang et al. 1995) in the adjacent/benign samples and 0% (Etkind et al. 2000) to 1.8% (Wang et al. 1995) in the normal controls.
Until now, a total of 03 studies (Morales-Sanchez et al. 2013; Cedro-Tanda et al. 2014; Zapata-Benavides et al. 2007) including two case–control study (Morales-Sanchez et al. 2013; Cedro-Tanda et al. 2014) have been reported in Mexico to determine the causal relationship between MMTV-like virus and BC. All these studies utilized PCR with primers specific for the Env gene-specific primers and the documented MMTV-like virus detection positivity ratios varied from 0% (Morales-Sanchez et al. 2013) to 12.6% (Cedro-Tanda et al. 2014) in BC samples and 0% (Morales-Sanchez et al. 2013) to 16% (Cedro-Tanda et al. 2014) in adjacent/benign controls.
A single study (San et al. 2017) has been conducted in Myanmar to date to relate the MMTV-like virus presence with BC. In total, they analyzed 58 BC samples were using PCR technique with primers specific for the Env region and documented a 1.7% 1.7% detection positivity ratio.
A total of 04 studies (Mazzanti et al. 2011; Naccarato et al. 2019; Pogo et al. 1999; Zammarchi et al. 2006) including a case–control study (Mazzanti et al. 2011) have been carried out in Italy so far, analyzing the etiological association between 1.7% and BC. These studies utilized the PCR technique with primers specific for the Env region of the viral genome and documented MMTV-like virus detection positivity ratios with varying frequencies ranging from 33% (Shariatpanahi et al. 2017) to 68.1% (Mazzanti et al. 2011) in BC samples, while 0% (Mazzanti et al. 2011) in normal and 19.2% (Mazzanti et al. 2011) in adjacent/benign controls.
In China, there has been a single study (Luo et al. 2006) reported so far to find out if MMTV-like virus is associated with BC. They utilized PCR technique with primers specifically targeting the Env sequence of the viral genome and documented 18.25% MMTV-like virus detection positivity ratio.