Aims: Experimental and clinical evidence demonstrate that progesterone hormone and its
nuclear receptor, the Progesterone Receptor (PR), play critical role in controlling mammary gland tumorigenesis
and breast cancer development. Hormonal therapy (Tomaxifen) is the frontline treatment
for hormone-dependent breast cancers. Progesterone hormone induces its action on the target cells by
binding with its Progesterone receptor (PgR) therefore any genetic variations, which might induce
alienation in the progesterone receptor, can result in an increased susceptibility of gynecological cancers.
Alu insertion (PROGINS) mutation in PgR gene is reported to be associated with an increased
risk of ovarian cancer and a decreased risk of breast cancer. However, its association with breast cancer
risk remains inconclusive. Therefore, we investigated the association of PROGINS allele and its
link with breast cancer risk.
Methods: This case control study was performed on 200 subjects in which 100 were breast cancer
cases and 100 gender matched healthy controls.The mutation was detected by using mutation specific
PCR and results were confirmed by direct Sanger sequencing.
Results: A clinically significant difference was reported in genotype distribution of PROGINs allele
among the cases and gender-matched healthy controls (P<0. 032). Genotype frequencies of A1/A1,
A1/A2, A2/A2 reported in cases was 81%, 19% (18% & 1%) and in matched healthy controls were
93%, 7% (6% & 1%). The higher frequency of PROGINs allele (19%) was observed in cases than the
healthy controls (7%). The findings indicated that PgR variants (CC vs CT) increased the risk of Breast
cancer in codominant inheritance model with OR= 3.44, 95% CI =1. 30-9.09, P<0.021) whereas nonsignificant
association was found for CC vs TT genotypes with OR=1.14, 95% CI=0.07-18.658, P=0.
92. However, subgroup analysis revealed that CT + TT vs CC genotype increased the risk of breast
cancer in dominant inheritance model tested OR = 3. 11, 95% CI = (1.24-7.79), P = 0.015). A nonsignificant
association for PgR (CC+CT) vs TT) genotypes were reported in breast cancer OR = 1. 0,
95% CI= (0. 061-16.21), P=1) in recessive inheritance model tested. However, analysis with clinicalpathological
variables revealed that the PROGINs allele is significantly associated with the distant
metastasis and advanced stage of the disease.
Conclusion: The mutation specific PCR was successfully developed as an alternative to Sanger sequencing
for the cost-effective detection for PROGINS allele of progesterone receptor gene. A clinically
significant correlation of PROGINs allele was reported with the distant metastasis and advanced
stage of the disease. Taken together, these results demonstrated that PROGINS variant is associated
with an increased susceptibility to Breast cancer, providing novel insights into the genetic etiology and
underlying biology of Breast carcinogenesis. Further studies with large sample sizes are required to
validate our findings.