Lack of HIN-1 methylation defines specific breast tumor subtypes including medullary carcinoma of the breast and BRCA1 linked tumors

Medullary carcinoma is a poorly differentiated breast cancer with a high histologic grade and a paradoxically good prognosis. It accounts for only 3% of all breast cancers except in BRCA-1 families, in which it can account for as many as 13% of cancers. To date, only histologic criteria have been used to define this tumor type. In an attempt to more clearly define the genetic pathway leading to this subtype of cancer, we recently demonstrated that nearly 100% of these carcinomas display p53 mutations. In the present study, we extended our analysis to include HIN-1, a candidate tumor suppressor that has been shown to be silenced by methylation in the majority of breast tumors. In striking contrast to unselected sporadic invasive ductal carcinoma, we show that medullary carcinomas do not display a high frequency of HIN-1 methylation (p<0.001). This feature is also found in BRCA-1 associated tumors that shared several histologic characteristics with medullary carcinomas of the breast. Medullary carcinoma of the breast should therefore be considered to be a unique entity defined by specific histologic and molecular traits.