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p53 and Breast cancer

Breast Cancer
Medullary Cancer of the Breast
p53 Mutation in Medullary Cancer of the Breast
Hin-1 Inactivation in MC and BRCA1 Family

Breast Cancer

Breast cancer is the third most common tumor in the world and represents 9% of the global cancer burden. This percentage varies considerably around the world: in high-risk areas, such as North America and western Europe, breast cancer accounts for one in four female cancers, while in low-risk areas such as China and Japan, it accounts for only one in eight to one in 16. The importance of environmental factors in the etiology of breast cancer is demonstrated by the change in risk in migrant populations. Rates of breast cancer in European migrants to the USA evolve relatively rapidly toward those of the US population, but changes in migrant populations from China and Japan are less rapid. Risks factors incudes family history, high fat diet, early age of menarche, nulliparity and late age of menopause.

for more information on breast cancer:
cancer.gov in US

Medullary cancer of the breast

Human breast tumors can classified into histopathological subtypes with distinct biological and prognostic characteristics. Among these, medullary cancer of the breast (MC) represents a minor morphologically and biologically distinct group (3-5% of breast cancer). Initially identified half a century ago as a favorable prognostic form, MC was classified by Ridolfi in 1977 as necessarily combining 5 features:

seemingly well-circumscribed histological limits,
syncytial architecture in at least 75% of the areas examined,
inflammation of the stroma containing lymphoplasmocytic infiltrate,
moderate or marked anisonucleosis
absence of tubular differentiation and/or an intraductal component.

Despite the fact that these tumors are histologic grade III, the prognosis is significantly more favorable than with the usual invasive breast carcinoma. Such observation have been linked to the lymphoplasmacytic cell infiltrate that could stimulate the host immune response. The genetic pathway that leads to MC has been largely unknown due to the low frequency of this tumor

Invasive Carcinomas of the Breast


p53 mutation in medullary breast cancer

Typical medullary carcinomas have at least 75% syncytial architecture, a well-defined border diffuse lymphoplasmocytic infiltrate, moderate or marked anisonucleosis and the absence of tubular differentiation and/or an intraductal component.
Atypical medullary carcinomas (8 of 23 specimens) have a syncytial architecture and two or three of the criteria above.

We assessed the status of the p53 gene with molecular and immunohistochemical techniques. Seventy percent (17 of 23) of tumors had a p53 mutation. Immunohistochemical analysis show that p53 accumulated in the 14 tumors containing either a missense mutation, an in frame one codon deletion or a long truncated protein.

Eight tumors were atypical medullary breast carcinoma and 15 tumors were typical medullary breast carcinoma. Interestingly, all typical medullary carcinomas harbored a p53 alteration (95% CI = 78-100%).In the eight atypical medullary carcinoma tumors examined, only two mutations were detected, giving a frequency of 25% (95% CI = 3-65%), a frequency similar to that for invasive breast carcinoma.



Our results indicate that medullary breast carcinoma is a distinct form of breast cancer. The observations that there is a high incidence of p53 alterations and an unambiguous pattern of p53 staining suggest that the genetic pathway leading to this subtype of cancer is different from that of common infiltrating breast carcinoma.

de Cremoux P, Salomon AV, Liva S, Dendale R, Bouchindhomme B, Martin E, et al. p53 mutation as a genetic trait of typical medullary breast carcinoma. J Nat Cancer Inst 1999; 91: 641-643. download the manuscript

Hin-1 inactivation in medullary breast cancer and BRCA1 tumors

Medullary carcinoma accounts for only 3% of all breast cancers except in BRCA-1 families where it can reach 13%. Thus far, only histologic criteria are used to define this tumor type.

 Among the new genes that have been recently characterized in breast tumors, HIN-1, a putative tumor suppressor gene of unknown function, have been shown to be silenced by methylation in the majority of sporadic breast carcinomas

We have extend our analysis to the analysis of HIN-1, a candidate tumor suppressor that have been shown to be silenced by methylation in the majority of breast tumors. In striking contrast to DCIS, 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 histological characteristics with medullary breast tumors. Therefore, we should consider medullary breast carcinoma a unique entity with specific histological and molecular traits.

Analysis of CpG island promoter methylation of hin-1 gene by MSP. MSP analysis was performed with either DCIS (A) or with MC (B). U and M indicates amplification using primers specific for un-methylated or methylated DNA respectively. U Ctl : amplification performed with normal DNA ; M Ctl : amplification performed with normal DNA methylated in vitro ; H2O : Control with no DNA ; MK : marker.


Tisserand P, Fouquet C, Barrois M, Gallou C, Dendale R, Stoppa-Lyonnet D, et al. Lack of HIN-1 Methylation Defines Specific Breast Tumor Subtypes Including Medullary Carcinoma of the Breast and BRCA1-Linked Tumors. Cancer Biol Ther 2003; 2: 559-63.download the manuscript


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