The patched polymorphism Pro1315Leu (C3944T) may modulate the association between use of oral contraceptives and breast cancer risk

Abstract

The gene coding for the human homologue of the Drosophila segment polarity gene patched (PTCH1) is mutated in several common human tumors. In mice, haplodeficiency at the Ptch1 locus results in severe histologic defects in mammary ductal structure. We found no mutations within the coding region of PTCH1 in 17 human primary breast carcinomas. However, the biallelic Pro1315Leu (C3944T ) polymorphism of PTCH1 was significantly associated with breast cancer in 41 Bavarian patients compared to 85 healthy controls. We investigated whether this variant influences susceptibility for breast cancer in 611 breast cancer patients diagnosed by age 50 years and 1,057 controls matched by age and study region in Germany and in 1,093 breast cancer patients from the United Kingdom. Allele and genotype frequencies were not different between cases and controls. However, multivariate logistic regression analysis revealed an effect modification of oral contraceptive use (OC) on breast cancer risk by Leu-carrier status. Compared to women who have Pro/Pro and never used OC, Pro/Pro OC users had an increased odds ratio for breast cancer of 1.7. The odds ratio was also 1.7 for Leu-carriers who never used OC, but this was attenuated among Leu-carriers who ever used OC by 20%. Key words: genetic polymorphism; breast cancer; gene-environment interaction; oral contraceptivesThe tumor suppressor gene PTCH1 is a downstream receptor in the hedgehog family of cell signaling proteins and plays an essential role in many aspects of cell growth and cell differentiation. Germline mutations in PTCH1 have been detected in patients with nevoid basal cell carcinoma syndrome (NBCCS), in which patients are predisposed to developmental abnormalities and a variety of neoplasms including basal cell carcinoma and medulloblastoma. 1,2 In addition, somatic mutations in PTCH1 have been identified in sporadic cases of basal cell carcinomas and of medulloblastoma and in a variety of other tumors (see review). 3,4 Interestingly, nonsense mutations in PTCH1 have been reported in 2 of 7 breast carcinomas, 5 suggesting an involvement of the SHH/PTCH1 signaling pathway in development of this kind of tumor. Although a similar study in a larger sample of 45 breast carcinomas did not reveal any inactivating PTCH1 mutations, 6 the possible involvement of this gene in the formation of breast carcinoma has also been demonstrated in an animal model for Ptch1 haplodeficiency. 7 All postpubescent virgin mice heterozygous for Ptch1 developed ductal hyperplasia and dysplasia of the mammary glands, which reverted during late pregnancy and lactation but returned upon involution and gland remodeling. Treatment with estradiol and progesterone enhanced the mutant histologic phenotype. These data suggest a role for the Ptch1 signaling network in mammary growth and differentiation.To obtain further insights into the involvement of PTCH1 in breast carcinoma formation, we analyzed a series of breast carcinomas for PTCH1 mutations. In the process we observed that the biallelic Pro1315Leu (...

Gli3-mediated repression of Hedgehog targets is required for normal mammary development

“…Moreover, our observations are entirely consistent with other studies reporting lack of Gli1 expression in normal human breast tissue (Kubo et al, 2004). Intriguingly, these studies reported Gli1 protein upregulation in 52/52 epithelial breast cancers and 4/6 epithelial breast tumor cell lines probably resulting from epigenetic regulatory events, as mutations in Hh pathway components are infrequent in breast tumors (Chang-Claude et al, 2003;Kubo et al, 2004;Vorechovsky et al, 1999;Wicking et al, 1998;Xie et al, 1997). Our results show that Gli3 is the only Gli expressed in normal lumenal epithelial cells.…”

Susceptibility to Basal Cell Carcinoma: Associations with PTCH Polymorphisms

“…The exon 23 3944 C/T change lies in the region that encodes part of the cytoplasmic domain and encodes a proline to leucine change, though the possible functional effects of the substitution are not known. This polymorphism has been linked with breast cancer risk in women using oral contraceptives (Chang-Claude et al 2003). Thus, these variants may have functional implications and plausibility.…”

Constitutive activation of smoothened (SMO) in mammary glands of transgenic mice leads to increased proliferation, altered differentiation and ductal dysplasia

“…An early study found Ptch1 mutations in two of seven human breast cancers (Xie et al, 1997). Additionally, a Ptch1 polymorphism was linked to increased breast cancer risk associated with oral contraceptive use (Chang-Claude et al, 2003). More recently, array comparative genomic hybridization (CGH) analyses indicate that genomic loss at the Ptch1 locus was the fourth most commonly detected change among the tumor suppressor genes identified in the study, occurring in 19% of human breast cancers and in 33% of breast cancer cell lines (Naylor et al, 2005).…”

“…Genetic analyses in mice indicate a role in mammary ductal morphogenesis, and recent data suggest a role in human mammary epithelial stem cell selfrenewal (Liu et al, 2006). In addition to hedgehog functions in normal development, altered hedgehog signaling is now implicated in approximately 20-25% of all cancers (Briscoe and Therond, 2005), and there is increasing evidence to suggest a role in breast cancer (Chang-Claude et al, 2003;Kubo et al, 2004;Lewis et al, 2001; Lewis et al, 1999;Liu et al, 2006;Mukherjee et al, 2006;Naylor et al, 2005). However, the specific roles hedgehog network genes play in normal mammary gland development remain unclear, and no experiments have been performed to test directly whether inappropriately activated hedgehog signaling has functional consequences for gland development, or causes breast cancer.…”